Minkyung Kwon, MD

Study Overview

Objective. To assess whether procalcitonin-guided antibiotic usage results in less exposure to antibiotics than usual care, without a significantly higher rate of adverse events.

Design. Multi-center 1:1 randomized trial.

Setting and participants. This study was conducted at 14 academic hospitals in the United States between 2014 and 2017 in which procalcitonin assay was not routinely used. All adult patients in the emergency department with an initial diagnosis of acute lower respiratory tract infection without a decision to give or withhold antibiotics because of uncertainty regarding the need for antibiotics were included in the study. Patients were excluded if antibiotics were unlikely to be held in their case, such as if there was a need for mechanical ventilation or known severe immunosuppression, and if procalcitonin could be falsely elevated (chronic dialysis, metastatic cancer, surgery in the past 7 days).

Intervention. Patients were randomly assigned to receive guideline-based care using procalcitonin (procalcitonin group) or usual care (usual-care group). In the procalcitonin group, the procalcitonin assay results, and the procalcitonin treatment guidelines were provided to the treating physician. The guideline used previously established cutoffs (procalcitonin level of < 0.1 µg/L, antibiotics were strongly discouraged; 0.1 to 0.25 µg/L, antibiotics were discouraged; 0.25 to 0.5 µg/L, antibiotics were recommended; and > 0.5 µg/L, antibiotics were strongly recommended). Procalcitonin was measured initially in the emergency department. If the patient was hospitalized, procalcitonin was again measured 6 to 24 hours later, and on hospital days 3, 5, and 7. To implement this intervention, a multifaceted approach was used, which included sending letters to local primary care providers describing the trial, ensuring rapid delivery of procalcitonin results by tracking and coordinating blood samples with routine morning draws, and embedding the procalcitonin results and guidelines into the sites’ electronic health records. In the usual-care group, procalcitonin levels at enrollment were measured but not disclosed to clinicians. In both treatment groups, clinicians retained autonomy regarding care decisions.

Main outcome measures. The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment. The primary safety outcome was any adverse effects that could be attributable to withholding antibiotics in lower respiratory tract infections, within 30 days after enrollment. Secondary outcomes included admission to the intensive care unit (ICU), subsequent emergency department visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.

Main results. 8360 patients with acute lower respiratory tract infection who presented to the emergency department were screened for eligibility; of these, 1664 patients underwent randomization. Ultimately, 1656 patients were included in the final analysis cohort (826 in the procalcitonin group and 830 in the usual-care group), because 8 patients withdrew. Of the cohort, 1345 (81.2%) patients completed the full 30-day follow up. Baseline characteristics were similar between the treatment groups. In the procalcitonin group, clinicians received the procalcitonin results for 95.9% of the patients. As a result of clinical care, 2.2% of the patients in the usual-care group also had procalcitonin testing. Clinicians adhered to the procalcitonin guideline recommendations for 64.8% of the procalcitonin group.

There was no significant difference in the intention-treat-treat analysis between the procalcitonin group and the usual-care group in antibiotic days during the first 30 days (mean antibiotic days, 4.2 and 4.3 days, respectively [95% confidence interval {CI}, –0.6 to 0.5; P = 0.87]). Within 30 days there was no significant difference in the proportion of patients with adverse outcomes in the procalcitonin group and usual-care group (11.7% and 13.1%, respectively [95% CI, –4.6 to 1.7]; P < 0.01 for noninferiority). There was no significant difference between the procalcitonin and usual-care groups for any of the secondary outcomes.

Conclusion. A procalcitonin-directed antibiotic administration guideline did not result in fewer antibiotic days than did usual-care among patients with suspected lower respiratory tract infection.

Commentary

Procalcitonin is a serum biomarker synthesized in thyroid neuroendocrine cells and is the precursor to calcitonin.¹ It is undetectable in healthy human serum, but in the setting of systemic inflammation caused by bacterial infection, procalcitonin synthesis is induced in many tissues. Since its discovery in 1970, procalcitonin’s potential utility has been sought in various settings, such as guiding the initiation and/or discontinuation of antibiotics.²

In a prospective randomized trial in patients with an acute chronic obstructive pulmonary disease (COPD) exacerbation, treatment success was not better with antibiotics than placebo in patients with a procalcitonin level < 0.1 µg/L.³ Others replicated these results in COPD patients with acute exacerbation of COPD.⁴ Another small randomized trial showed that using procalcitonin in intensive care patients reduced antibiotic duration.⁵ Another small study found similar results in their critical care setting.⁶ Procalcitonin-guided antibiotic treatment produced similar results in patients with aspiration pneumonia.⁷ In summary, previously published studies nearly uniformly report reduced antibiotic duration or initiation using procalcitonin cutoffs without increasing adverse events.

In the current study, Huang and colleagues conducted a multi-center randomized trial in 14 academic US hospitals, while simultaneously attempting quality improvement methods for implementing and maximizing compliance with procalcitonin guidelines for local physicians. This study was able to achieve approximately 65% compliance with the guideline, which is relatively lower than in previously reported studies using procalcitonin guidelines. This study was larger and involved more hospitals than the other studies. Interestingly, this study did not find statistically significant differences in antibiotic usage or duration between the procalcitonin group compared to the usual-care group. While this result can be partially explained by the low rate of compliance with the guideline, the result may actually reflect the real-life pattern of procalcitonin guideline usage in clinicians. These results suggest that procalcitonin-based guidelines attempting to reduce antibiotic usage and exposure may be of low value, contrasting with findings from previous studies.

The Huang et al study is well-designed, had a low rate of follow-up loss and withdrawal, was conducted mostly at urban academic hospitals that had a high level of adherence to Joint Commission pneumonia core measures, and had appropriate statistical analyses; however, several factors should be considered when applying the results of this study to clinical practice. First, the large majority (80.1%) of the study cohort had final diagnoses of a COPD exacerbation, asthma exacerbation, or acute bronchitis. These patients had a moderate degree of disease (required hospitalization in 59% of patients with a mean hospital length of stay of 5 days), but their symptoms were severe enough for the patients to present to the emergency department. Patients with a suspected nonrespiratory infection or a milder degree of infection, especially in the ambulatory care setting, may have different antibiotic prescribing patterns. Also, patients in the ambulatory care setting likely have different causal organisms of their diagnosis. Second, this study excluded patients with severe disease who required ICU admission with either septic shock or respiratory failure, patients with pre-existing diseases that placed them at high risk (eg, immunosuppressed patients), and/or patients who had complications of their infection with either a lung abscess or empyema. This pattern of exclusion was widely similar to the other previous procalcitonin studies, which shows that procalcitonin guidelines should not be applied blindly in critically ill patients, even those not requiring ICU admission. Third, patients were excluded from the study if they were on chronic dialysis, had metastatic cancer, or had a recent surgery because of possible elevation of procalcitonin levels without a bacterial infection.

In conclusion, the current study did not find any difference in antibiotic exposure throughout the course of care (including discharge or hospitalization) of patients with a lower respiratory tract infection who presented to the emergency department when a procalcitonin guideline was implemented. The results of the current study raise questions regarding the new trend of widely accepting procalcitonin-based antibiotic usage.

Applications for Clinical Practice

Procalcitonin is a relatively new marker that is released during a systemic bacterial infection. While prior studies have supported systematic use of procalcitonin-based guidelines to initiate and discontinue antibiotics in order to limit antibiotic exposure, clinicians should be mindful that a procalcitonin antibiotic guideline may be useful in specific patients and should only be used in combination with usual clinical judgment. Clinicians must also recognize the medical conditions that may falsely elevate the procalcitonin level. Most important, the procalcitonin level should not be used as the sole indication to withhold antibiotics in an otherwise appropriately indicated clinical scenario.

—Minkyung Kwon, MD, Scott A. Helgeson, MD, and Vichaya Arunthari, MD
Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To assess whether procalcitonin-guided antibiotic usage results in less exposure to antibiotics than usual care, without a significantly higher rate of adverse events.

Design. Multi-center 1:1 randomized trial.

Setting and participants. This study was conducted at 14 academic hospitals in the United States between 2014 and 2017 in which procalcitonin assay was not routinely used. All adult patients in the emergency department with an initial diagnosis of acute lower respiratory tract infection without a decision to give or withhold antibiotics because of uncertainty regarding the need for antibiotics were included in the study. Patients were excluded if antibiotics were unlikely to be held in their case, such as if there was a need for mechanical ventilation or known severe immunosuppression, and if procalcitonin could be falsely elevated (chronic dialysis, metastatic cancer, surgery in the past 7 days).

Intervention. Patients were randomly assigned to receive guideline-based care using procalcitonin (procalcitonin group) or usual care (usual-care group). In the procalcitonin group, the procalcitonin assay results, and the procalcitonin treatment guidelines were provided to the treating physician. The guideline used previously established cutoffs (procalcitonin level of < 0.1 µg/L, antibiotics were strongly discouraged; 0.1 to 0.25 µg/L, antibiotics were discouraged; 0.25 to 0.5 µg/L, antibiotics were recommended; and > 0.5 µg/L, antibiotics were strongly recommended). Procalcitonin was measured initially in the emergency department. If the patient was hospitalized, procalcitonin was again measured 6 to 24 hours later, and on hospital days 3, 5, and 7. To implement this intervention, a multifaceted approach was used, which included sending letters to local primary care providers describing the trial, ensuring rapid delivery of procalcitonin results by tracking and coordinating blood samples with routine morning draws, and embedding the procalcitonin results and guidelines into the sites’ electronic health records. In the usual-care group, procalcitonin levels at enrollment were measured but not disclosed to clinicians. In both treatment groups, clinicians retained autonomy regarding care decisions.

Main outcome measures. The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment. The primary safety outcome was any adverse effects that could be attributable to withholding antibiotics in lower respiratory tract infections, within 30 days after enrollment. Secondary outcomes included admission to the intensive care unit (ICU), subsequent emergency department visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.

Main results. 8360 patients with acute lower respiratory tract infection who presented to the emergency department were screened for eligibility; of these, 1664 patients underwent randomization. Ultimately, 1656 patients were included in the final analysis cohort (826 in the procalcitonin group and 830 in the usual-care group), because 8 patients withdrew. Of the cohort, 1345 (81.2%) patients completed the full 30-day follow up. Baseline characteristics were similar between the treatment groups. In the procalcitonin group, clinicians received the procalcitonin results for 95.9% of the patients. As a result of clinical care, 2.2% of the patients in the usual-care group also had procalcitonin testing. Clinicians adhered to the procalcitonin guideline recommendations for 64.8% of the procalcitonin group.

There was no significant difference in the intention-treat-treat analysis between the procalcitonin group and the usual-care group in antibiotic days during the first 30 days (mean antibiotic days, 4.2 and 4.3 days, respectively [95% confidence interval {CI}, –0.6 to 0.5; P = 0.87]). Within 30 days there was no significant difference in the proportion of patients with adverse outcomes in the procalcitonin group and usual-care group (11.7% and 13.1%, respectively [95% CI, –4.6 to 1.7]; P < 0.01 for noninferiority). There was no significant difference between the procalcitonin and usual-care groups for any of the secondary outcomes.

Conclusion. A procalcitonin-directed antibiotic administration guideline did not result in fewer antibiotic days than did usual-care among patients with suspected lower respiratory tract infection.

Commentary

Procalcitonin is a serum biomarker synthesized in thyroid neuroendocrine cells and is the precursor to calcitonin.¹ It is undetectable in healthy human serum, but in the setting of systemic inflammation caused by bacterial infection, procalcitonin synthesis is induced in many tissues. Since its discovery in 1970, procalcitonin’s potential utility has been sought in various settings, such as guiding the initiation and/or discontinuation of antibiotics.²

In a prospective randomized trial in patients with an acute chronic obstructive pulmonary disease (COPD) exacerbation, treatment success was not better with antibiotics than placebo in patients with a procalcitonin level < 0.1 µg/L.³ Others replicated these results in COPD patients with acute exacerbation of COPD.⁴ Another small randomized trial showed that using procalcitonin in intensive care patients reduced antibiotic duration.⁵ Another small study found similar results in their critical care setting.⁶ Procalcitonin-guided antibiotic treatment produced similar results in patients with aspiration pneumonia.⁷ In summary, previously published studies nearly uniformly report reduced antibiotic duration or initiation using procalcitonin cutoffs without increasing adverse events.

In the current study, Huang and colleagues conducted a multi-center randomized trial in 14 academic US hospitals, while simultaneously attempting quality improvement methods for implementing and maximizing compliance with procalcitonin guidelines for local physicians. This study was able to achieve approximately 65% compliance with the guideline, which is relatively lower than in previously reported studies using procalcitonin guidelines. This study was larger and involved more hospitals than the other studies. Interestingly, this study did not find statistically significant differences in antibiotic usage or duration between the procalcitonin group compared to the usual-care group. While this result can be partially explained by the low rate of compliance with the guideline, the result may actually reflect the real-life pattern of procalcitonin guideline usage in clinicians. These results suggest that procalcitonin-based guidelines attempting to reduce antibiotic usage and exposure may be of low value, contrasting with findings from previous studies.

The Huang et al study is well-designed, had a low rate of follow-up loss and withdrawal, was conducted mostly at urban academic hospitals that had a high level of adherence to Joint Commission pneumonia core measures, and had appropriate statistical analyses; however, several factors should be considered when applying the results of this study to clinical practice. First, the large majority (80.1%) of the study cohort had final diagnoses of a COPD exacerbation, asthma exacerbation, or acute bronchitis. These patients had a moderate degree of disease (required hospitalization in 59% of patients with a mean hospital length of stay of 5 days), but their symptoms were severe enough for the patients to present to the emergency department. Patients with a suspected nonrespiratory infection or a milder degree of infection, especially in the ambulatory care setting, may have different antibiotic prescribing patterns. Also, patients in the ambulatory care setting likely have different causal organisms of their diagnosis. Second, this study excluded patients with severe disease who required ICU admission with either septic shock or respiratory failure, patients with pre-existing diseases that placed them at high risk (eg, immunosuppressed patients), and/or patients who had complications of their infection with either a lung abscess or empyema. This pattern of exclusion was widely similar to the other previous procalcitonin studies, which shows that procalcitonin guidelines should not be applied blindly in critically ill patients, even those not requiring ICU admission. Third, patients were excluded from the study if they were on chronic dialysis, had metastatic cancer, or had a recent surgery because of possible elevation of procalcitonin levels without a bacterial infection.

In conclusion, the current study did not find any difference in antibiotic exposure throughout the course of care (including discharge or hospitalization) of patients with a lower respiratory tract infection who presented to the emergency department when a procalcitonin guideline was implemented. The results of the current study raise questions regarding the new trend of widely accepting procalcitonin-based antibiotic usage.

Applications for Clinical Practice

Procalcitonin is a relatively new marker that is released during a systemic bacterial infection. While prior studies have supported systematic use of procalcitonin-based guidelines to initiate and discontinue antibiotics in order to limit antibiotic exposure, clinicians should be mindful that a procalcitonin antibiotic guideline may be useful in specific patients and should only be used in combination with usual clinical judgment. Clinicians must also recognize the medical conditions that may falsely elevate the procalcitonin level. Most important, the procalcitonin level should not be used as the sole indication to withhold antibiotics in an otherwise appropriately indicated clinical scenario.

—Minkyung Kwon, MD, Scott A. Helgeson, MD, and Vichaya Arunthari, MD
Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To assess whether procalcitonin-guided antibiotic usage results in less exposure to antibiotics than usual care, without a significantly higher rate of adverse events.

Design. Multi-center 1:1 randomized trial.

Setting and participants. This study was conducted at 14 academic hospitals in the United States between 2014 and 2017 in which procalcitonin assay was not routinely used. All adult patients in the emergency department with an initial diagnosis of acute lower respiratory tract infection without a decision to give or withhold antibiotics because of uncertainty regarding the need for antibiotics were included in the study. Patients were excluded if antibiotics were unlikely to be held in their case, such as if there was a need for mechanical ventilation or known severe immunosuppression, and if procalcitonin could be falsely elevated (chronic dialysis, metastatic cancer, surgery in the past 7 days).

Intervention. Patients were randomly assigned to receive guideline-based care using procalcitonin (procalcitonin group) or usual care (usual-care group). In the procalcitonin group, the procalcitonin assay results, and the procalcitonin treatment guidelines were provided to the treating physician. The guideline used previously established cutoffs (procalcitonin level of < 0.1 µg/L, antibiotics were strongly discouraged; 0.1 to 0.25 µg/L, antibiotics were discouraged; 0.25 to 0.5 µg/L, antibiotics were recommended; and > 0.5 µg/L, antibiotics were strongly recommended). Procalcitonin was measured initially in the emergency department. If the patient was hospitalized, procalcitonin was again measured 6 to 24 hours later, and on hospital days 3, 5, and 7. To implement this intervention, a multifaceted approach was used, which included sending letters to local primary care providers describing the trial, ensuring rapid delivery of procalcitonin results by tracking and coordinating blood samples with routine morning draws, and embedding the procalcitonin results and guidelines into the sites’ electronic health records. In the usual-care group, procalcitonin levels at enrollment were measured but not disclosed to clinicians. In both treatment groups, clinicians retained autonomy regarding care decisions.

Main outcome measures. The primary outcome was total antibiotic exposure, defined as the total number of antibiotic-days within 30 days after enrollment. The primary safety outcome was any adverse effects that could be attributable to withholding antibiotics in lower respiratory tract infections, within 30 days after enrollment. Secondary outcomes included admission to the intensive care unit (ICU), subsequent emergency department visits by day 30, and quality of life as assessed with the Airway Questionnaire 20.

Main results. 8360 patients with acute lower respiratory tract infection who presented to the emergency department were screened for eligibility; of these, 1664 patients underwent randomization. Ultimately, 1656 patients were included in the final analysis cohort (826 in the procalcitonin group and 830 in the usual-care group), because 8 patients withdrew. Of the cohort, 1345 (81.2%) patients completed the full 30-day follow up. Baseline characteristics were similar between the treatment groups. In the procalcitonin group, clinicians received the procalcitonin results for 95.9% of the patients. As a result of clinical care, 2.2% of the patients in the usual-care group also had procalcitonin testing. Clinicians adhered to the procalcitonin guideline recommendations for 64.8% of the procalcitonin group.

There was no significant difference in the intention-treat-treat analysis between the procalcitonin group and the usual-care group in antibiotic days during the first 30 days (mean antibiotic days, 4.2 and 4.3 days, respectively [95% confidence interval {CI}, –0.6 to 0.5; P = 0.87]). Within 30 days there was no significant difference in the proportion of patients with adverse outcomes in the procalcitonin group and usual-care group (11.7% and 13.1%, respectively [95% CI, –4.6 to 1.7]; P < 0.01 for noninferiority). There was no significant difference between the procalcitonin and usual-care groups for any of the secondary outcomes.

Conclusion. A procalcitonin-directed antibiotic administration guideline did not result in fewer antibiotic days than did usual-care among patients with suspected lower respiratory tract infection.

Commentary

Procalcitonin is a serum biomarker synthesized in thyroid neuroendocrine cells and is the precursor to calcitonin.¹ It is undetectable in healthy human serum, but in the setting of systemic inflammation caused by bacterial infection, procalcitonin synthesis is induced in many tissues. Since its discovery in 1970, procalcitonin’s potential utility has been sought in various settings, such as guiding the initiation and/or discontinuation of antibiotics.²

In a prospective randomized trial in patients with an acute chronic obstructive pulmonary disease (COPD) exacerbation, treatment success was not better with antibiotics than placebo in patients with a procalcitonin level < 0.1 µg/L.³ Others replicated these results in COPD patients with acute exacerbation of COPD.⁴ Another small randomized trial showed that using procalcitonin in intensive care patients reduced antibiotic duration.⁵ Another small study found similar results in their critical care setting.⁶ Procalcitonin-guided antibiotic treatment produced similar results in patients with aspiration pneumonia.⁷ In summary, previously published studies nearly uniformly report reduced antibiotic duration or initiation using procalcitonin cutoffs without increasing adverse events.

In the current study, Huang and colleagues conducted a multi-center randomized trial in 14 academic US hospitals, while simultaneously attempting quality improvement methods for implementing and maximizing compliance with procalcitonin guidelines for local physicians. This study was able to achieve approximately 65% compliance with the guideline, which is relatively lower than in previously reported studies using procalcitonin guidelines. This study was larger and involved more hospitals than the other studies. Interestingly, this study did not find statistically significant differences in antibiotic usage or duration between the procalcitonin group compared to the usual-care group. While this result can be partially explained by the low rate of compliance with the guideline, the result may actually reflect the real-life pattern of procalcitonin guideline usage in clinicians. These results suggest that procalcitonin-based guidelines attempting to reduce antibiotic usage and exposure may be of low value, contrasting with findings from previous studies.

The Huang et al study is well-designed, had a low rate of follow-up loss and withdrawal, was conducted mostly at urban academic hospitals that had a high level of adherence to Joint Commission pneumonia core measures, and had appropriate statistical analyses; however, several factors should be considered when applying the results of this study to clinical practice. First, the large majority (80.1%) of the study cohort had final diagnoses of a COPD exacerbation, asthma exacerbation, or acute bronchitis. These patients had a moderate degree of disease (required hospitalization in 59% of patients with a mean hospital length of stay of 5 days), but their symptoms were severe enough for the patients to present to the emergency department. Patients with a suspected nonrespiratory infection or a milder degree of infection, especially in the ambulatory care setting, may have different antibiotic prescribing patterns. Also, patients in the ambulatory care setting likely have different causal organisms of their diagnosis. Second, this study excluded patients with severe disease who required ICU admission with either septic shock or respiratory failure, patients with pre-existing diseases that placed them at high risk (eg, immunosuppressed patients), and/or patients who had complications of their infection with either a lung abscess or empyema. This pattern of exclusion was widely similar to the other previous procalcitonin studies, which shows that procalcitonin guidelines should not be applied blindly in critically ill patients, even those not requiring ICU admission. Third, patients were excluded from the study if they were on chronic dialysis, had metastatic cancer, or had a recent surgery because of possible elevation of procalcitonin levels without a bacterial infection.

In conclusion, the current study did not find any difference in antibiotic exposure throughout the course of care (including discharge or hospitalization) of patients with a lower respiratory tract infection who presented to the emergency department when a procalcitonin guideline was implemented. The results of the current study raise questions regarding the new trend of widely accepting procalcitonin-based antibiotic usage.

Applications for Clinical Practice

Procalcitonin is a relatively new marker that is released during a systemic bacterial infection. While prior studies have supported systematic use of procalcitonin-based guidelines to initiate and discontinue antibiotics in order to limit antibiotic exposure, clinicians should be mindful that a procalcitonin antibiotic guideline may be useful in specific patients and should only be used in combination with usual clinical judgment. Clinicians must also recognize the medical conditions that may falsely elevate the procalcitonin level. Most important, the procalcitonin level should not be used as the sole indication to withhold antibiotics in an otherwise appropriately indicated clinical scenario.

—Minkyung Kwon, MD, Scott A. Helgeson, MD, and Vichaya Arunthari, MD
Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To determine if nocturnal dexmedetomidine prevents delirium and improves sleep in critically ill patients.

Design. Two-center, double-blind, placebo-controlled, randomized, trial.

Setting and participants. This study was conducted in the intensive care units (ICU) at 2 centers in North America between 2013 and 2016. Adults admitted to the ICU and receiving intermittent or continuous sedatives and expected to require at least 48 hours of ICU care were included in the study. Exclusion criteria were presence of delirium, severe dementia, acute neurologic injury, severe bradycardia, hepatic encephalopathy, end-stage liver disease, and expected death within 24 hours.

Intervention. Patients were randomized 1:1 to receive nocturnal dexmedetomidine (0.2–0.7 mcg/kg/hr) or dextrose 5% in water. Patients, clinicians, bedside nurses, and all study personnel were blinded to study drug assignment throughout the study. All sedatives were halved before the study drug was administered each evening. As-needed intravenous midazolam was used while titrating up the study drug. Study drug was administered nightly until either ICU discharge or an adverse event occurred. Decisions regarding use of other analgesic and sedative therapy, including opioids, oral benzodiazepines, acetaminophen, and nonsteroidal anti-inflammatory drugs, were left to the discretion of the clinician. Sleep-promoting agents such as melatonin or trazodone were not allowed.

Main outcome measures. The primary outcome was the proportion of patients who remained free of delirium during their critical illness. Secondary outcomes included ICU days spent without delirium; duration of delirium; sleep quality; proportion of patients who ever developed coma; proportion of nocturnal hours spent at each Richmond Agitation and Sedation Scale (RASS) score; maximal nocturnal pain levels; antipsychotic, corticosteroid, and oral analgesic use; days of mechanical ventilation; ICU and hospital stay duration; and ICU and hospital mortality.

Main results. 100 patients were randomized, with 50 patients in each group. 89% of patients were mechanically ventilated, and the Prediction of Delirium in ICU (PRE-DELIRIC) score [1] was 54 in the dexmedetomidine group and 51 in the placebo group. Continuous propofol and fentanyl infusion at randomization was used in 49% and 80%, respectively. Duration of median ICU stay was 10 days in the dexmedetomidine group and 9 days in the placebo group. More patients in the dexmedetomidine group (40 of 50 patients [80%]) than in the placebo group (27 of 50 patients [54%]) remained free of delirium (relative risk [RR], 0.44, 95% confidence interval {CI} 0.23 to 0.82; P = 0.006). The median (interquartile range [IQR]) duration of the first episode of delirium was similar between the dexmedetomidine (IQR 2.0 [0.6–2.7] days) and placebo (2.2 [0.7–3.2] days) groups (P = 0.73). The average Leeds Sleep Evaluation Questionnaire score also was similar (mean difference, 0.02, 95% CI 0.42 to 1.92) between the 2 groups. Incidence of hypotension or bradycardia did not differ significantly between the groups.

Conclusion. Nocturnal administration of low-dose dexmedetomidine in critically ill adults reduces the incidence of delirium during the ICU stay, and patient-reported sleep quality appears unchanged.

Delirium is a sudden state of confusion and/or disturbance of consciousness and cognition that is believed to result from acute brain dysfunction, including neurochemical disequilibrium. It often occurs in association with a general medical condition, such as various types of shock, sepsis, surgery, anesthesia, or electrolyte imbalance. Studies have shown that delirium is associated with increased mortality in critically ill patients [2]. Most ICUs use a systematic assessment tool for early detection of delirium, such as the Confusion Assessment Method for the ICU (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICDSC), or the DSM-IV TR score system. The CAM-ICU is the most frequently used tool to evaluate for the presence of delirium in critically ill patients; it is scored as positive if the patient manifests both an acute change in mental status and inattention, and has either a RASS greater than 0 or disorganized thinking [3].

The level of evidence regarding delirium prevention is low. Ear plugs, eye masks, educational staff, supportive reorientation, and music have been studied as nonpharmacologic methods for preventing delirium [4]. From a pharmacologic standpoint, the dopamine D2 antagonist haloperidol has been explored as a therapy for both treating and preventing delirium, since the condition is thought to be associated with anticholinergic and excessive dopaminergic mechanisms. A randomized controlled study in 142 patients who received haloperidol 2.5 mg intravenously every 8 hours found that the duration of delirium did not differ between the haloperidol and the placebo groups [5]. The most feared adverse effects of haloperidol, such as akathisia, muscle stiffness, arrhythmia, or QT prolongation, did not occur more frequently in the haloperidol group. Similar results have been reported by Al-Qadheeb et al [6]. Pharmacologic prophylaxis of delirium using atypical antipsychotics such as quetiapine has also been explored, but the level of evidence for this intervention remains very low. Current American College of Critical Care Medicine guidelines recommend nonpharmacologic management and do not firmly recommend any pharmacologic prevention for ICU delirium [7].

Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist that acts at the locus ceruleus, providing sedation and analgesia. Studies assessing the choice of sedation in the ICU found that the use of dexmedetomidine or propofol, compared to benzodiazepines, is associated with a lower rate of delirium occurrence, especially in mechanically ventilated patients [8,9]. Dexmedetomidine offers several potential advantages over other sedative drugs: it has little effect on cognition, has minimal anticholinergic effect, and may restore a natural sleep pattern. While propofol causes hypotension, respiratory depression, and deeper sedation, dexmedetomidine is associated with lighter sedation, a minimal effect on respiratory drive, and a milder hemodynamic effect. In a randomized controlled trial involving post-surgery ICU patients, dexmedetomidine partially restored a normal sleep pattern (eg, increased percentage of stage 2 non-rapid eye movement sleep), prolonged total sleep time, improved sleep efficiency, and increased sleep quality [10]; by improving overall sleep quality, dexmedetomidine potentially may prevent delirium. Another study that randomly assigned 700 ICU patients who underwent noncardiac surgery to dexmedetomidine infusion (0.1 mcg/kg/hr from ICU admission on the day of surgery until the following morning) or placebo reported a significantly reduced incidence of delirium in the dexmedetomidine group [11]. On the other hand, a 2015 Cochrane meta-analysis that included 7 randomized controlled studies did not find a significant risk reduction of delirium with dexmedetomidine [12].

The current study by Skrobik et al was a randomized, placebo-controlled trial that examined the role of nocturnal dexmedetomidine in ICU delirium prevention in 100 ICU patients. Nocturnal administration of low-dose dexmedetomidine led to a statistically significant reduction in delirium incidence compared to placebo (RR of delirium, 0.44, 95% CI 0.23 to 0.82, which is similar to that suggested by previous studies). This study adds additional evidence regarding the use of dexmedetomidine for pharmacologic delirium prevention. It included many mechanically ventilated patients (89% of study population), strengthening the applicability of the result. Mechanical ventilation is a known risk factor for ICU delirium, and therefore this is an important population to study; previous trials largely included patients who were not mechanically ventilated. This study also supports the safety of dexmedetomidine infusion, especially in lower doses in critically ill patients, without significantly increasing the incidence of adverse events (mainly hypotension and bradycardia). The study protocol closely approximated real practice by allowing other analgesics, including opioids, and therefore suggests safety and real world applicability.

There are several confounding issues in this study. The study was blinded, and there was concern that the bedside nurses may have been able to identify the study drug based on the effects on heart rate. In addition, 50% of patients received antipsychotics. While baseline RASS score was significantly different between the 2 groups, patients in the dexmedetomidine group reached a deeper level of sedation during the study. Also, the protocol mandated halving the pre-existing sedative on the night of study drug initiation, which could have led to inadequate sedation in the placebo group. Placebo patients received propofol for a similar duration but at a higher dose compared to dexmedetomidine patients, and midazolam and fentanyl infusion was used in a similar pattern between the groups. The high exclusion rate (71%) limits the ability to generalize the results to all ICU patients.

Applications for Clinical Practice

ICU delirium is an important complication of critical illness and is potentially preventable. Benzodiazepines are associated with an increased risk of delirium, while there has been increasing interest in dexmedetomidine, a selective alpha-2 adrenergic receptor agonist, because of its potential for delirium prevention. Evidence to date does not strongly support routine use of pharmacologic prevention of delirium; however, dexmedetomidine may be an option for sedation, as opposed to benzodiazepines or propofol, in selected patients and may potentially prevent delirium.

—Minkyung Kwon, MD, Neal Patel, MD, and Vichaya Arunthari, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL

Study Overview

Objective. To evaluate the efficacy and safety of Zephyr endobronchial valves (EBVs) in patients with heterogeneous emphysema and absence of collateral ventilation.

Design. Multicenter, randomized, nonblinded clinical trial.

Setting and participants. This study was conducted at 17 sites across Europe between 2014 and 2016. Patients with severe emphysema who were ex-smokers and ≥ 40 years old were recruited. Key inclusion criteria were post-bronchodilator FEV1 between 15%–45% predicted despite optimal medical management, total lung capacity greater than 100% predicted, residual volume ≥ 180% predicted, and a 6-minute walk distance of between 150 and 450 meters. Heterogenous emphysema was defined as a greater than 10% difference in destruction score between target and ipsilateral lobes as measured by high-resolution CT. All eligible patients underwent Chartis pulmonary assessment (Pulmonx, Redwood City, CA) assessment to determine the presence of collateral ventilation between the target and adjacent lobes, and patients with collateral ventilation were excluded.

Intervention. Patients were randomized 2:1 to either EBV plus standard of care (intervention) or standard of care alone (control) by blocked design and concealed envelopes. The EBV group underwent immediate placement of Zephyr EBVs with the intention of complete lobar occlusion.

Main outcome measures. The primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute walk distance, St. George’s Respiratory Questionnaire score and modified Medical Research Council score were assessed at 3 and 6 months and target lobe volume reduction on chest CT at 3 months.

Main results. 97 subjects were randomized to the intervention (n = 65) or control group (n = 32). At 3 months, 55.4% of intervention and 6.5% of control subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: intervention, 56.3%, versus control, 3.2% (P < 0.001), with a mean ± SD change in FEV1% at 6 months of 20.7 ± 29.6% and –8.6 ± 13.0%, respectively. A total of 89.8% of intervention subjects had target lobe volume reduction greater than or equal to 350 mL (mean, 1.09 ± 0.62 L; P < 0.001). The differences in outcomes between the intervention and control groups were statistically significant, with the following measured differences: residual volume, –700 m; 6-minute walk distance, +78.7 m; St. George’s Respiratory Questionnaire score, –6.5 points; modified Medical Research Council dyspnea score, –0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, –1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of intervention subjects.

Conclusion. Endobronchial valve treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance and quality of life, with an acceptable safety profile.

Commentary

Patients with severe emphysema are difficult to manage. Optimal medical management is required to maintain their lung function and quality of life, with combination bronchodilators (long-acting beta 2 agonists, long-acting anticholinergics, and inhaled corticosteroids), roflumilast (selective phosphodiesterase-4 inhibitors), oral corticosteroids or macrolide antibiotics when indicated, long-term oxygen, and noninvasive ventilator support. Palliative team care consultation and support, adequate nutritional support, influenza and pneumococcal vaccination, and pulmonary rehabilitation/graded exercise training are important aspects of emphysema treatment [1].

To help patients with severe emphysema who experience further decline despite intensive medical management, a lung volume reduction strategy was devised. In 2003, the NETT trial was conducted [2]. In this study, lung volume reduction surgery was performed in 608 patients, who were followed for 29 months. This study revealed a lack of survival benefit with significant immediate postoperative mortality and complication rate. Despite this disappointing result, a subgroup of patients (upper-lobe predominant disease and low baseline exercise capacity) had a statistically significant mortality benefit from surgery.

Since then, many have sought to determine a less invasive method of lung volume reduction. So far, one-way endobronchial valves, self-activating coils, and targeted destruction and remodeling of emphysematous lung with vapor or sealant methods have been studied. Several studies have examined the efficacy and safety of coils, with reasonable improvement of 6-minute walk distance and FEV1; however, complications including death, pneumothorax and pneumonia were noted. Vapor ablation (STEP-UP trial) [3] and lung sealant [4] were also attempted in order to achieve lung volume reduction, but increased infection was problematic. The 2017 GOLD guidelines suggested lung volume reduction by endobronchial one-way valve or lung coils as interventional bronchoscopic options for lung volume reduction [1].

Two types of endobronchial valves have been introduced to date: the intra bronchial valve, developed by Olympus, and the Zephyr valve by Pulmonx. Endobronchial valves are deployed to the bronchi via bronchoscopic guidance, and limit airflow to the portions of the lung distal to the valve while allowing mucus and air movement in the proximal direction. The VENT study, the largest endobronchial valve trial using the Zephyr valve, was published in 2010 [5]. This study demonstrated the efficacy of endobronchial valve treatment, especially in patients with heterogeneous emphysema and complete interlobar fissures as opposed to homogeneous emphysema and incomplete interlobar fissures. Subsequent studies demonstrated the importance of absence of collateral ventilation, measured by the Chartis system, when considering endobronchial valves [6].

The current study by Kemp et al is the first multicenter randomized endobronchial valve trial conducted in Europe. The study was able to demonstrate remarkable improvement in FEV1 (mean 140 mL decrease vs 90 mL increase) and 6-minute walk distance (mean +36.2 meter vs –42.5 meter) after endobronchial valve treatment in severe emphysema patients. The amount of volume reduction was reaching up to 2 liters. Patients in the control group were given the opportunity to receive endobronchial valve after the 6 months study follow-up period and 30 out of 32 patients opted for the endobronchial valve treatment. The authors concluded that the endobronchial valve therapy resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance and quality of life with an acceptable safety profile.

It is notable that the authors included only selected patients, limited to those with presence of heterogeneous emphysema, absence of collateral ventilation, low risk of COPD exacerbation or infection, and patients who were likely able to tolerate pneumothorax. Despite this, 13 patients developed pneumothorax and death occurred in 1 patient, leading to a significantly longer average length of hospital stay in the treatment group. Although this rate of complications is not higher than prior endobronchial valve studies, it is important to note when broadly applying the outcomes of this study to patient care. Lack of long-term follow-up and the nonblinded study design also limit the strength of this study.

Applications for Clinical Practice

Many patients suffer from emphysema. Among them, severe emphysema is the most difficult to manage. It is important to incorporate optimal medical management including bronchodilators, palliative care, oxygen therapy, pulmonary rehabilitation and non-invasive ventilation options. When patients with severe emphysema continue to decline or seek further improvement in their care, and when they meet the specific criteria for lung volume reduction, endobronchial valve therapy should be considered an option and physicians should refer them to appropriate centers. However, the risk of complications, such as pneumothorax, still remains high.

—Minkyung Kwon, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL, and Joel Roberson, MD, Department of Radiology, William Beaumont Hospital, Royal Oak, MI

Study Overview

Objective. To evaluate the efficacy and safety of Zephyr endobronchial valves (EBVs) in patients with heterogeneous emphysema and absence of collateral ventilation.

Design. Multicenter, randomized, nonblinded clinical trial.

Setting and participants. This study was conducted at 17 sites across Europe between 2014 and 2016. Patients with severe emphysema who were ex-smokers and ≥ 40 years old were recruited. Key inclusion criteria were post-bronchodilator FEV1 between 15%–45% predicted despite optimal medical management, total lung capacity greater than 100% predicted, residual volume ≥ 180% predicted, and a 6-minute walk distance of between 150 and 450 meters. Heterogenous emphysema was defined as a greater than 10% difference in destruction score between target and ipsilateral lobes as measured by high-resolution CT. All eligible patients underwent Chartis pulmonary assessment (Pulmonx, Redwood City, CA) assessment to determine the presence of collateral ventilation between the target and adjacent lobes, and patients with collateral ventilation were excluded.

Intervention. Patients were randomized 2:1 to either EBV plus standard of care (intervention) or standard of care alone (control) by blocked design and concealed envelopes. The EBV group underwent immediate placement of Zephyr EBVs with the intention of complete lobar occlusion.

Main outcome measures. The primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute walk distance, St. George’s Respiratory Questionnaire score and modified Medical Research Council score were assessed at 3 and 6 months and target lobe volume reduction on chest CT at 3 months.

Main results. 97 subjects were randomized to the intervention (n = 65) or control group (n = 32). At 3 months, 55.4% of intervention and 6.5% of control subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: intervention, 56.3%, versus control, 3.2% (P < 0.001), with a mean ± SD change in FEV1% at 6 months of 20.7 ± 29.6% and –8.6 ± 13.0%, respectively. A total of 89.8% of intervention subjects had target lobe volume reduction greater than or equal to 350 mL (mean, 1.09 ± 0.62 L; P < 0.001). The differences in outcomes between the intervention and control groups were statistically significant, with the following measured differences: residual volume, –700 m; 6-minute walk distance, +78.7 m; St. George’s Respiratory Questionnaire score, –6.5 points; modified Medical Research Council dyspnea score, –0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, –1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of intervention subjects.

Conclusion. Endobronchial valve treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance and quality of life, with an acceptable safety profile.

Commentary

Patients with severe emphysema are difficult to manage. Optimal medical management is required to maintain their lung function and quality of life, with combination bronchodilators (long-acting beta 2 agonists, long-acting anticholinergics, and inhaled corticosteroids), roflumilast (selective phosphodiesterase-4 inhibitors), oral corticosteroids or macrolide antibiotics when indicated, long-term oxygen, and noninvasive ventilator support. Palliative team care consultation and support, adequate nutritional support, influenza and pneumococcal vaccination, and pulmonary rehabilitation/graded exercise training are important aspects of emphysema treatment [1].

To help patients with severe emphysema who experience further decline despite intensive medical management, a lung volume reduction strategy was devised. In 2003, the NETT trial was conducted [2]. In this study, lung volume reduction surgery was performed in 608 patients, who were followed for 29 months. This study revealed a lack of survival benefit with significant immediate postoperative mortality and complication rate. Despite this disappointing result, a subgroup of patients (upper-lobe predominant disease and low baseline exercise capacity) had a statistically significant mortality benefit from surgery.

Since then, many have sought to determine a less invasive method of lung volume reduction. So far, one-way endobronchial valves, self-activating coils, and targeted destruction and remodeling of emphysematous lung with vapor or sealant methods have been studied. Several studies have examined the efficacy and safety of coils, with reasonable improvement of 6-minute walk distance and FEV1; however, complications including death, pneumothorax and pneumonia were noted. Vapor ablation (STEP-UP trial) [3] and lung sealant [4] were also attempted in order to achieve lung volume reduction, but increased infection was problematic. The 2017 GOLD guidelines suggested lung volume reduction by endobronchial one-way valve or lung coils as interventional bronchoscopic options for lung volume reduction [1].

Two types of endobronchial valves have been introduced to date: the intra bronchial valve, developed by Olympus, and the Zephyr valve by Pulmonx. Endobronchial valves are deployed to the bronchi via bronchoscopic guidance, and limit airflow to the portions of the lung distal to the valve while allowing mucus and air movement in the proximal direction. The VENT study, the largest endobronchial valve trial using the Zephyr valve, was published in 2010 [5]. This study demonstrated the efficacy of endobronchial valve treatment, especially in patients with heterogeneous emphysema and complete interlobar fissures as opposed to homogeneous emphysema and incomplete interlobar fissures. Subsequent studies demonstrated the importance of absence of collateral ventilation, measured by the Chartis system, when considering endobronchial valves [6].

The current study by Kemp et al is the first multicenter randomized endobronchial valve trial conducted in Europe. The study was able to demonstrate remarkable improvement in FEV1 (mean 140 mL decrease vs 90 mL increase) and 6-minute walk distance (mean +36.2 meter vs –42.5 meter) after endobronchial valve treatment in severe emphysema patients. The amount of volume reduction was reaching up to 2 liters. Patients in the control group were given the opportunity to receive endobronchial valve after the 6 months study follow-up period and 30 out of 32 patients opted for the endobronchial valve treatment. The authors concluded that the endobronchial valve therapy resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance and quality of life with an acceptable safety profile.

It is notable that the authors included only selected patients, limited to those with presence of heterogeneous emphysema, absence of collateral ventilation, low risk of COPD exacerbation or infection, and patients who were likely able to tolerate pneumothorax. Despite this, 13 patients developed pneumothorax and death occurred in 1 patient, leading to a significantly longer average length of hospital stay in the treatment group. Although this rate of complications is not higher than prior endobronchial valve studies, it is important to note when broadly applying the outcomes of this study to patient care. Lack of long-term follow-up and the nonblinded study design also limit the strength of this study.

Applications for Clinical Practice

Many patients suffer from emphysema. Among them, severe emphysema is the most difficult to manage. It is important to incorporate optimal medical management including bronchodilators, palliative care, oxygen therapy, pulmonary rehabilitation and non-invasive ventilation options. When patients with severe emphysema continue to decline or seek further improvement in their care, and when they meet the specific criteria for lung volume reduction, endobronchial valve therapy should be considered an option and physicians should refer them to appropriate centers. However, the risk of complications, such as pneumothorax, still remains high.

—Minkyung Kwon, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL, and Joel Roberson, MD, Department of Radiology, William Beaumont Hospital, Royal Oak, MI

Study Overview

Objective. To evaluate the efficacy and safety of Zephyr endobronchial valves (EBVs) in patients with heterogeneous emphysema and absence of collateral ventilation.

Design. Multicenter, randomized, nonblinded clinical trial.

Setting and participants. This study was conducted at 17 sites across Europe between 2014 and 2016. Patients with severe emphysema who were ex-smokers and ≥ 40 years old were recruited. Key inclusion criteria were post-bronchodilator FEV1 between 15%–45% predicted despite optimal medical management, total lung capacity greater than 100% predicted, residual volume ≥ 180% predicted, and a 6-minute walk distance of between 150 and 450 meters. Heterogenous emphysema was defined as a greater than 10% difference in destruction score between target and ipsilateral lobes as measured by high-resolution CT. All eligible patients underwent Chartis pulmonary assessment (Pulmonx, Redwood City, CA) assessment to determine the presence of collateral ventilation between the target and adjacent lobes, and patients with collateral ventilation were excluded.

Intervention. Patients were randomized 2:1 to either EBV plus standard of care (intervention) or standard of care alone (control) by blocked design and concealed envelopes. The EBV group underwent immediate placement of Zephyr EBVs with the intention of complete lobar occlusion.

Main outcome measures. The primary outcome at 3 months post-procedure was the percentage of subjects with FEV1 improvement from baseline of 12% or greater. Changes in FEV1, residual volume, 6-minute walk distance, St. George’s Respiratory Questionnaire score and modified Medical Research Council score were assessed at 3 and 6 months and target lobe volume reduction on chest CT at 3 months.

Main results. 97 subjects were randomized to the intervention (n = 65) or control group (n = 32). At 3 months, 55.4% of intervention and 6.5% of control subjects had an FEV1 improvement of 12% or more (P < 0.001). Improvements were maintained at 6 months: intervention, 56.3%, versus control, 3.2% (P < 0.001), with a mean ± SD change in FEV1% at 6 months of 20.7 ± 29.6% and –8.6 ± 13.0%, respectively. A total of 89.8% of intervention subjects had target lobe volume reduction greater than or equal to 350 mL (mean, 1.09 ± 0.62 L; P < 0.001). The differences in outcomes between the intervention and control groups were statistically significant, with the following measured differences: residual volume, –700 m; 6-minute walk distance, +78.7 m; St. George’s Respiratory Questionnaire score, –6.5 points; modified Medical Research Council dyspnea score, –0.6 points; and BODE (body mass index, airflow obstruction, dyspnea, and exercise capacity) index, –1.8 points (all P < 0.05). Pneumothorax was the most common adverse event, occurring in 19 of 65 (29.2%) of intervention subjects.

Conclusion. Endobronchial valve treatment in hyperinflated patients with heterogeneous emphysema without collateral ventilation resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance and quality of life, with an acceptable safety profile.

Commentary

Patients with severe emphysema are difficult to manage. Optimal medical management is required to maintain their lung function and quality of life, with combination bronchodilators (long-acting beta 2 agonists, long-acting anticholinergics, and inhaled corticosteroids), roflumilast (selective phosphodiesterase-4 inhibitors), oral corticosteroids or macrolide antibiotics when indicated, long-term oxygen, and noninvasive ventilator support. Palliative team care consultation and support, adequate nutritional support, influenza and pneumococcal vaccination, and pulmonary rehabilitation/graded exercise training are important aspects of emphysema treatment [1].

To help patients with severe emphysema who experience further decline despite intensive medical management, a lung volume reduction strategy was devised. In 2003, the NETT trial was conducted [2]. In this study, lung volume reduction surgery was performed in 608 patients, who were followed for 29 months. This study revealed a lack of survival benefit with significant immediate postoperative mortality and complication rate. Despite this disappointing result, a subgroup of patients (upper-lobe predominant disease and low baseline exercise capacity) had a statistically significant mortality benefit from surgery.

Since then, many have sought to determine a less invasive method of lung volume reduction. So far, one-way endobronchial valves, self-activating coils, and targeted destruction and remodeling of emphysematous lung with vapor or sealant methods have been studied. Several studies have examined the efficacy and safety of coils, with reasonable improvement of 6-minute walk distance and FEV1; however, complications including death, pneumothorax and pneumonia were noted. Vapor ablation (STEP-UP trial) [3] and lung sealant [4] were also attempted in order to achieve lung volume reduction, but increased infection was problematic. The 2017 GOLD guidelines suggested lung volume reduction by endobronchial one-way valve or lung coils as interventional bronchoscopic options for lung volume reduction [1].

Two types of endobronchial valves have been introduced to date: the intra bronchial valve, developed by Olympus, and the Zephyr valve by Pulmonx. Endobronchial valves are deployed to the bronchi via bronchoscopic guidance, and limit airflow to the portions of the lung distal to the valve while allowing mucus and air movement in the proximal direction. The VENT study, the largest endobronchial valve trial using the Zephyr valve, was published in 2010 [5]. This study demonstrated the efficacy of endobronchial valve treatment, especially in patients with heterogeneous emphysema and complete interlobar fissures as opposed to homogeneous emphysema and incomplete interlobar fissures. Subsequent studies demonstrated the importance of absence of collateral ventilation, measured by the Chartis system, when considering endobronchial valves [6].

The current study by Kemp et al is the first multicenter randomized endobronchial valve trial conducted in Europe. The study was able to demonstrate remarkable improvement in FEV1 (mean 140 mL decrease vs 90 mL increase) and 6-minute walk distance (mean +36.2 meter vs –42.5 meter) after endobronchial valve treatment in severe emphysema patients. The amount of volume reduction was reaching up to 2 liters. Patients in the control group were given the opportunity to receive endobronchial valve after the 6 months study follow-up period and 30 out of 32 patients opted for the endobronchial valve treatment. The authors concluded that the endobronchial valve therapy resulted in clinically meaningful benefits in lung function, dyspnea, exercise tolerance and quality of life with an acceptable safety profile.

It is notable that the authors included only selected patients, limited to those with presence of heterogeneous emphysema, absence of collateral ventilation, low risk of COPD exacerbation or infection, and patients who were likely able to tolerate pneumothorax. Despite this, 13 patients developed pneumothorax and death occurred in 1 patient, leading to a significantly longer average length of hospital stay in the treatment group. Although this rate of complications is not higher than prior endobronchial valve studies, it is important to note when broadly applying the outcomes of this study to patient care. Lack of long-term follow-up and the nonblinded study design also limit the strength of this study.

Applications for Clinical Practice

Many patients suffer from emphysema. Among them, severe emphysema is the most difficult to manage. It is important to incorporate optimal medical management including bronchodilators, palliative care, oxygen therapy, pulmonary rehabilitation and non-invasive ventilation options. When patients with severe emphysema continue to decline or seek further improvement in their care, and when they meet the specific criteria for lung volume reduction, endobronchial valve therapy should be considered an option and physicians should refer them to appropriate centers. However, the risk of complications, such as pneumothorax, still remains high.

—Minkyung Kwon, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL, and Joel Roberson, MD, Department of Radiology, William Beaumont Hospital, Royal Oak, MI

Study Overview

Objective. To determine if an intervention directed toward early detection of pulmonary exacerbations using electronic home monitoring of spirometry and symptoms would result in slower decline in lung function.

Design. Multicenter, randomized, nonblinded 2-arm clinical trial.

Setting and participants. The study was conducted at 14 cystic fibrosis centers in the United States between 2011 and 2015. Cystic fibrosis patients (stable at baseline, FEV1 > 25% predicted) at least 14 years old (adolescent and adults) were included and randomized 1:1 to either an early intervention arm or usual care arm.

Intervention. The intervention arm used home-based spirometers and patient-reported respiratory symptoms using the Cystic Fibrosis Respiratory Symptoms Diary (CFRSD), which was to be completed twice weekly and collected by the central AM2 system. This AM2 system alerted sites to contact patients for an acute pulmonary exacerbation evaluation when FEV1 values fell by greater than 10% from baseline or CFRSD worsened from baseline in two or more of eight respiratory symptoms. The usual care arm patients had quarterly CF visits and/or acute visits based on their need.

Main outcome measures. The primary outcome variable was the 52-week change in FEV1 volume in liters. Secondary outcome variables were changes in CFQ-R (Cystic Fibrosis Questionnaire, revised), CFRSD, FEV1 % predicted, FVC in liters, FEF25-75%, time to first acute pulmonary exacerbation, time from first pulmonary exacerbation to subsequent pulmonary exacerbation, number of hospitalization days, number of hospitalizations, percent change in prevalence of Pseudomonas or Staphylococcus aureus and global assessment of protocol burden score.

Main results. A total of 267 patients were randomized. The results were analyzed using intention-to-treat analysis. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, –0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations sooner and more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 94% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms.

Conclusion. An intervention of electronic home monitoring of patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function.

Commentary

Establishing efficacy and safety of home monitoring is a popular research topic in the current era of information technology. Most data to date has come from chronic adult disease such as heart failure, diabetes, or COPD [1]. While relatively rare, CF is a chronic lung disease that could potentially benefit from home monitoring. This is supported by previous evidence suggesting that up to a quarter of pulmonary exacerbations in CF patients result in worsened baseline lung function [2]. Close monitoring of symptoms and FEV1 using home monitoring was hypothesized to improve management and long-term function in this population. Indeed, in children with CF, electronic home monitoring of symptoms and lung function was able to detect pulmonary exacerbations early [3]. Frequency of monitoring is widely variable between centers, and some suggest aggressive monitoring of CF provides better clinical outcomes [4]. Current CF guidelines do not make specific recommendations regarding frequency of monitoring.

In this study, Lechtzin et al attempted to determine if the early detection of acute pulmonary exacerbations in CF patients by home monitoring and treatment would prevent progressive decline in lung function. This multicenter randomized trial was conducted at large CF centers in the US with a total cohort of 267 patients. The study had a mean follow-up time of 46.8 weeks per participant in the intervention arm and a mean follow-up time of 50.9 weeks per participant in the usual care arm. Given the predefined follow-up length (52 weeks) the primary outcome of FEV1 in liters was deemed sensitive enough to detect a decline of lung function. However the discrepancy between follow-up times with the intervention group having a 4.1-week shorter mean follow-up than the usual care could have influenced the interpretation of the results. Additionally, a large percentage of these patients were clinically stable at initial enrollment, with an average FEV1 % predicted of 79.5%. The stability of initial participants raises questions as to the efficacy of home monitoring in CF patient with moderate to severe lung disease. Mostly importantly, due to the nature of intervention the study could not be blinded, which could have substantially increased anxiety and self-awareness of patients in reporting their symptoms in the intervention arm.

Currently, an established consensus definition of pulmonary exacerbations of CF is lacking. Previous studies have proposed several different criteria of acute pulmonary exacerbations. Most proposed definitions depend on symptom changes such as cough, sputum, chest pain, shortness of breath, fatigue and weight-loss, making the definition less specific or objective.

The number of acute visits in the intervention arm was significantly higher than that in the usual care arm (153 vs 64). Despite a higher number of visits with intervention group, a significant number of these visits did not lead to a diagnosis of acute pulmonary exacerbation. Reportedly, 108 acute visits met protocol-defined pulmonary exacerbation and 29 acute visits did not meet protocol-defined pulmonary exacerbation in the intervention arm compared to 44 and 12 respectively in the usual care arm of the study. Given that the groups had similar baseline demographics and were randomized appropriately, one would expect that the number of acute visits severe enough to meet protocol-defined criteria as a pulmonary exacerbation would be similar in both groups. However, the absolute number of protocol-defined pulmonary exacerbations was far greater in the intervention group. Therefore, one could question the clinical significance of what was defined as acute pulmonary exacerbation. Potentially, the elevation of the absolute number of protocol-defined pulmonary exacerbations in the intervention group was simply due to increased surveillance. If the former were correct, one would expect the lack of identification/treatment of a significant number of pulmonary exacerbations in the usual care group would have led to a larger decline in FEV1 after 52 weeks than was seen in the results when compared to the intervention group. Given that the results of the study indicate no significant difference in change in FEV1 between study arms, perhaps the studied parameters in the intervention group were overly sensitive.

Of note, the usual care arm did have a statistically significant higher rate of hospitalizations and IV antibiotic use, suggesting that early identification of acute visits can identify patients earlier in the course of an acute pulmonary exacerbation and prevent higher level of care, though at the expense of more acute event “false positives,” or over-diagnosis. This trade-off may not result in cost saving, though this was not a consideration of this study. Additionally, there was likely difference in treatment, as treatment was not standardized, with potential implications for the validity of results.

The early intervention protocol was not only shown to lead to increased visits with no benefit in lung function decline, but as one may expect, also proved to be remarkably burdensome to many patients compared to the usual care protocol. Entering data on a weekly basis (or perhaps even monthly) was found to be burdensome in many remote-monitoring trials [5]. This may be especially apparent in a younger age group: in this study the average age of the study population was between 18 and 30 years of age. It can be hypothesized that this age group may not have enough responsibility, time, or enthusiasm to participate in home monitoring. Home monitoring maybe more effective in a disease condition where the average age is older or in a pediatric population in whom the parents oversee the care of the patient or have more time and receive subjective benefit from home monitoring services.

Less may be sufficient. The current study suggests that the home monitoring in CF may increase medical expense and unnecessary antibiotic use with no improvement in lung function. It is difficult to assess from this study the impact that the burden of home monitoring would have on clinical outcomes, however, previous meta-analysis of data studying COPD populations using home monitoring system, interestingly, also had increased health service usage and even led to increase in mortality in the intervention group compared with usual care group [1,6].

Perhaps the negative result of current study is due to the oftentimes variable definitions of and management algorithms for pulmonary exacerbations rather than the home monitoring system itself. Limited evidence exists for optimal threshold identification [7]. Aggregated, large amounts of data gathered by telemonitoring have not been proven to be used effectively. Moreover, as mentioned, a clear definition and management guidelines for pulmonary exacerbation are lacking. As a next step, studies are ongoing to evaluate how to use the collected data without increasing harm or cost. This could utilize machine learning or developing a more specific model defining and predicting pulmonary exacerbations as well as standardized indications for antibiotic therapy and hospitalization.

Applications for Clinical Practice

CF patients suffer from frequent pulmonary exacerbations and close monitoring and appropriate treatment is necessary to prevent progressive decline of lung function. This study has shown no benefit of electronic home monitoring in CF patients based on symptoms and spirometry over usual care. However, this negative outcome may be due to the limitation of the current definition of pulmonary exacerbation and lack of a consensus management algorithm. Optimizing the definition of pulmonary exacerbation and protocoling management based on severity may improve future evaluations of electronic home monitoring. Electronic home monitoring may help identify patients requiring evaluation; however, clinicians should continue to manage CF patients with conventional tools including regular follow-up visits, thorough history taking, and appropriate use of antibiotics based on their clinical acumen.

—Minkyung Kwon, MD, Joel Roberson, MD, Drew Willey, MD, and Neal Patel, MD (Mayo Clinic Florida, Jacksonville, FL, except for Dr. Roberson, of Oakland University/ Beaumont Health, Royal Oak, MI)

Study Overview

Objective. To determine if an intervention directed toward early detection of pulmonary exacerbations using electronic home monitoring of spirometry and symptoms would result in slower decline in lung function.

Design. Multicenter, randomized, nonblinded 2-arm clinical trial.

Setting and participants. The study was conducted at 14 cystic fibrosis centers in the United States between 2011 and 2015. Cystic fibrosis patients (stable at baseline, FEV1 > 25% predicted) at least 14 years old (adolescent and adults) were included and randomized 1:1 to either an early intervention arm or usual care arm.

Intervention. The intervention arm used home-based spirometers and patient-reported respiratory symptoms using the Cystic Fibrosis Respiratory Symptoms Diary (CFRSD), which was to be completed twice weekly and collected by the central AM2 system. This AM2 system alerted sites to contact patients for an acute pulmonary exacerbation evaluation when FEV1 values fell by greater than 10% from baseline or CFRSD worsened from baseline in two or more of eight respiratory symptoms. The usual care arm patients had quarterly CF visits and/or acute visits based on their need.

Main outcome measures. The primary outcome variable was the 52-week change in FEV1 volume in liters. Secondary outcome variables were changes in CFQ-R (Cystic Fibrosis Questionnaire, revised), CFRSD, FEV1 % predicted, FVC in liters, FEF25-75%, time to first acute pulmonary exacerbation, time from first pulmonary exacerbation to subsequent pulmonary exacerbation, number of hospitalization days, number of hospitalizations, percent change in prevalence of Pseudomonas or Staphylococcus aureus and global assessment of protocol burden score.

Main results. A total of 267 patients were randomized. The results were analyzed using intention-to-treat analysis. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, –0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations sooner and more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 94% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms.

Conclusion. An intervention of electronic home monitoring of patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function.

Commentary

Establishing efficacy and safety of home monitoring is a popular research topic in the current era of information technology. Most data to date has come from chronic adult disease such as heart failure, diabetes, or COPD [1]. While relatively rare, CF is a chronic lung disease that could potentially benefit from home monitoring. This is supported by previous evidence suggesting that up to a quarter of pulmonary exacerbations in CF patients result in worsened baseline lung function [2]. Close monitoring of symptoms and FEV1 using home monitoring was hypothesized to improve management and long-term function in this population. Indeed, in children with CF, electronic home monitoring of symptoms and lung function was able to detect pulmonary exacerbations early [3]. Frequency of monitoring is widely variable between centers, and some suggest aggressive monitoring of CF provides better clinical outcomes [4]. Current CF guidelines do not make specific recommendations regarding frequency of monitoring.

In this study, Lechtzin et al attempted to determine if the early detection of acute pulmonary exacerbations in CF patients by home monitoring and treatment would prevent progressive decline in lung function. This multicenter randomized trial was conducted at large CF centers in the US with a total cohort of 267 patients. The study had a mean follow-up time of 46.8 weeks per participant in the intervention arm and a mean follow-up time of 50.9 weeks per participant in the usual care arm. Given the predefined follow-up length (52 weeks) the primary outcome of FEV1 in liters was deemed sensitive enough to detect a decline of lung function. However the discrepancy between follow-up times with the intervention group having a 4.1-week shorter mean follow-up than the usual care could have influenced the interpretation of the results. Additionally, a large percentage of these patients were clinically stable at initial enrollment, with an average FEV1 % predicted of 79.5%. The stability of initial participants raises questions as to the efficacy of home monitoring in CF patient with moderate to severe lung disease. Mostly importantly, due to the nature of intervention the study could not be blinded, which could have substantially increased anxiety and self-awareness of patients in reporting their symptoms in the intervention arm.

Currently, an established consensus definition of pulmonary exacerbations of CF is lacking. Previous studies have proposed several different criteria of acute pulmonary exacerbations. Most proposed definitions depend on symptom changes such as cough, sputum, chest pain, shortness of breath, fatigue and weight-loss, making the definition less specific or objective.

The number of acute visits in the intervention arm was significantly higher than that in the usual care arm (153 vs 64). Despite a higher number of visits with intervention group, a significant number of these visits did not lead to a diagnosis of acute pulmonary exacerbation. Reportedly, 108 acute visits met protocol-defined pulmonary exacerbation and 29 acute visits did not meet protocol-defined pulmonary exacerbation in the intervention arm compared to 44 and 12 respectively in the usual care arm of the study. Given that the groups had similar baseline demographics and were randomized appropriately, one would expect that the number of acute visits severe enough to meet protocol-defined criteria as a pulmonary exacerbation would be similar in both groups. However, the absolute number of protocol-defined pulmonary exacerbations was far greater in the intervention group. Therefore, one could question the clinical significance of what was defined as acute pulmonary exacerbation. Potentially, the elevation of the absolute number of protocol-defined pulmonary exacerbations in the intervention group was simply due to increased surveillance. If the former were correct, one would expect the lack of identification/treatment of a significant number of pulmonary exacerbations in the usual care group would have led to a larger decline in FEV1 after 52 weeks than was seen in the results when compared to the intervention group. Given that the results of the study indicate no significant difference in change in FEV1 between study arms, perhaps the studied parameters in the intervention group were overly sensitive.

Of note, the usual care arm did have a statistically significant higher rate of hospitalizations and IV antibiotic use, suggesting that early identification of acute visits can identify patients earlier in the course of an acute pulmonary exacerbation and prevent higher level of care, though at the expense of more acute event “false positives,” or over-diagnosis. This trade-off may not result in cost saving, though this was not a consideration of this study. Additionally, there was likely difference in treatment, as treatment was not standardized, with potential implications for the validity of results.

The early intervention protocol was not only shown to lead to increased visits with no benefit in lung function decline, but as one may expect, also proved to be remarkably burdensome to many patients compared to the usual care protocol. Entering data on a weekly basis (or perhaps even monthly) was found to be burdensome in many remote-monitoring trials [5]. This may be especially apparent in a younger age group: in this study the average age of the study population was between 18 and 30 years of age. It can be hypothesized that this age group may not have enough responsibility, time, or enthusiasm to participate in home monitoring. Home monitoring maybe more effective in a disease condition where the average age is older or in a pediatric population in whom the parents oversee the care of the patient or have more time and receive subjective benefit from home monitoring services.

Less may be sufficient. The current study suggests that the home monitoring in CF may increase medical expense and unnecessary antibiotic use with no improvement in lung function. It is difficult to assess from this study the impact that the burden of home monitoring would have on clinical outcomes, however, previous meta-analysis of data studying COPD populations using home monitoring system, interestingly, also had increased health service usage and even led to increase in mortality in the intervention group compared with usual care group [1,6].

Perhaps the negative result of current study is due to the oftentimes variable definitions of and management algorithms for pulmonary exacerbations rather than the home monitoring system itself. Limited evidence exists for optimal threshold identification [7]. Aggregated, large amounts of data gathered by telemonitoring have not been proven to be used effectively. Moreover, as mentioned, a clear definition and management guidelines for pulmonary exacerbation are lacking. As a next step, studies are ongoing to evaluate how to use the collected data without increasing harm or cost. This could utilize machine learning or developing a more specific model defining and predicting pulmonary exacerbations as well as standardized indications for antibiotic therapy and hospitalization.

Applications for Clinical Practice

CF patients suffer from frequent pulmonary exacerbations and close monitoring and appropriate treatment is necessary to prevent progressive decline of lung function. This study has shown no benefit of electronic home monitoring in CF patients based on symptoms and spirometry over usual care. However, this negative outcome may be due to the limitation of the current definition of pulmonary exacerbation and lack of a consensus management algorithm. Optimizing the definition of pulmonary exacerbation and protocoling management based on severity may improve future evaluations of electronic home monitoring. Electronic home monitoring may help identify patients requiring evaluation; however, clinicians should continue to manage CF patients with conventional tools including regular follow-up visits, thorough history taking, and appropriate use of antibiotics based on their clinical acumen.

—Minkyung Kwon, MD, Joel Roberson, MD, Drew Willey, MD, and Neal Patel, MD (Mayo Clinic Florida, Jacksonville, FL, except for Dr. Roberson, of Oakland University/ Beaumont Health, Royal Oak, MI)

Study Overview

Objective. To determine if an intervention directed toward early detection of pulmonary exacerbations using electronic home monitoring of spirometry and symptoms would result in slower decline in lung function.

Design. Multicenter, randomized, nonblinded 2-arm clinical trial.

Setting and participants. The study was conducted at 14 cystic fibrosis centers in the United States between 2011 and 2015. Cystic fibrosis patients (stable at baseline, FEV1 > 25% predicted) at least 14 years old (adolescent and adults) were included and randomized 1:1 to either an early intervention arm or usual care arm.

Intervention. The intervention arm used home-based spirometers and patient-reported respiratory symptoms using the Cystic Fibrosis Respiratory Symptoms Diary (CFRSD), which was to be completed twice weekly and collected by the central AM2 system. This AM2 system alerted sites to contact patients for an acute pulmonary exacerbation evaluation when FEV1 values fell by greater than 10% from baseline or CFRSD worsened from baseline in two or more of eight respiratory symptoms. The usual care arm patients had quarterly CF visits and/or acute visits based on their need.

Main outcome measures. The primary outcome variable was the 52-week change in FEV1 volume in liters. Secondary outcome variables were changes in CFQ-R (Cystic Fibrosis Questionnaire, revised), CFRSD, FEV1 % predicted, FVC in liters, FEF25-75%, time to first acute pulmonary exacerbation, time from first pulmonary exacerbation to subsequent pulmonary exacerbation, number of hospitalization days, number of hospitalizations, percent change in prevalence of Pseudomonas or Staphylococcus aureus and global assessment of protocol burden score.

Main results. A total of 267 patients were randomized. The results were analyzed using intention-to-treat analysis. There was no significant difference between study arms in 52-week mean change in FEV1 slope (mean slope difference, 0.00 L, 95% confidence interval, –0.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations sooner and more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 94% confidence interval, 1.09 to 1.93; P = 0.01). Adverse events were not significantly different between treatment arms.

Conclusion. An intervention of electronic home monitoring of patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function.

Commentary

Establishing efficacy and safety of home monitoring is a popular research topic in the current era of information technology. Most data to date has come from chronic adult disease such as heart failure, diabetes, or COPD [1]. While relatively rare, CF is a chronic lung disease that could potentially benefit from home monitoring. This is supported by previous evidence suggesting that up to a quarter of pulmonary exacerbations in CF patients result in worsened baseline lung function [2]. Close monitoring of symptoms and FEV1 using home monitoring was hypothesized to improve management and long-term function in this population. Indeed, in children with CF, electronic home monitoring of symptoms and lung function was able to detect pulmonary exacerbations early [3]. Frequency of monitoring is widely variable between centers, and some suggest aggressive monitoring of CF provides better clinical outcomes [4]. Current CF guidelines do not make specific recommendations regarding frequency of monitoring.

In this study, Lechtzin et al attempted to determine if the early detection of acute pulmonary exacerbations in CF patients by home monitoring and treatment would prevent progressive decline in lung function. This multicenter randomized trial was conducted at large CF centers in the US with a total cohort of 267 patients. The study had a mean follow-up time of 46.8 weeks per participant in the intervention arm and a mean follow-up time of 50.9 weeks per participant in the usual care arm. Given the predefined follow-up length (52 weeks) the primary outcome of FEV1 in liters was deemed sensitive enough to detect a decline of lung function. However the discrepancy between follow-up times with the intervention group having a 4.1-week shorter mean follow-up than the usual care could have influenced the interpretation of the results. Additionally, a large percentage of these patients were clinically stable at initial enrollment, with an average FEV1 % predicted of 79.5%. The stability of initial participants raises questions as to the efficacy of home monitoring in CF patient with moderate to severe lung disease. Mostly importantly, due to the nature of intervention the study could not be blinded, which could have substantially increased anxiety and self-awareness of patients in reporting their symptoms in the intervention arm.

Currently, an established consensus definition of pulmonary exacerbations of CF is lacking. Previous studies have proposed several different criteria of acute pulmonary exacerbations. Most proposed definitions depend on symptom changes such as cough, sputum, chest pain, shortness of breath, fatigue and weight-loss, making the definition less specific or objective.

The number of acute visits in the intervention arm was significantly higher than that in the usual care arm (153 vs 64). Despite a higher number of visits with intervention group, a significant number of these visits did not lead to a diagnosis of acute pulmonary exacerbation. Reportedly, 108 acute visits met protocol-defined pulmonary exacerbation and 29 acute visits did not meet protocol-defined pulmonary exacerbation in the intervention arm compared to 44 and 12 respectively in the usual care arm of the study. Given that the groups had similar baseline demographics and were randomized appropriately, one would expect that the number of acute visits severe enough to meet protocol-defined criteria as a pulmonary exacerbation would be similar in both groups. However, the absolute number of protocol-defined pulmonary exacerbations was far greater in the intervention group. Therefore, one could question the clinical significance of what was defined as acute pulmonary exacerbation. Potentially, the elevation of the absolute number of protocol-defined pulmonary exacerbations in the intervention group was simply due to increased surveillance. If the former were correct, one would expect the lack of identification/treatment of a significant number of pulmonary exacerbations in the usual care group would have led to a larger decline in FEV1 after 52 weeks than was seen in the results when compared to the intervention group. Given that the results of the study indicate no significant difference in change in FEV1 between study arms, perhaps the studied parameters in the intervention group were overly sensitive.

Of note, the usual care arm did have a statistically significant higher rate of hospitalizations and IV antibiotic use, suggesting that early identification of acute visits can identify patients earlier in the course of an acute pulmonary exacerbation and prevent higher level of care, though at the expense of more acute event “false positives,” or over-diagnosis. This trade-off may not result in cost saving, though this was not a consideration of this study. Additionally, there was likely difference in treatment, as treatment was not standardized, with potential implications for the validity of results.

The early intervention protocol was not only shown to lead to increased visits with no benefit in lung function decline, but as one may expect, also proved to be remarkably burdensome to many patients compared to the usual care protocol. Entering data on a weekly basis (or perhaps even monthly) was found to be burdensome in many remote-monitoring trials [5]. This may be especially apparent in a younger age group: in this study the average age of the study population was between 18 and 30 years of age. It can be hypothesized that this age group may not have enough responsibility, time, or enthusiasm to participate in home monitoring. Home monitoring maybe more effective in a disease condition where the average age is older or in a pediatric population in whom the parents oversee the care of the patient or have more time and receive subjective benefit from home monitoring services.

Less may be sufficient. The current study suggests that the home monitoring in CF may increase medical expense and unnecessary antibiotic use with no improvement in lung function. It is difficult to assess from this study the impact that the burden of home monitoring would have on clinical outcomes, however, previous meta-analysis of data studying COPD populations using home monitoring system, interestingly, also had increased health service usage and even led to increase in mortality in the intervention group compared with usual care group [1,6].

Perhaps the negative result of current study is due to the oftentimes variable definitions of and management algorithms for pulmonary exacerbations rather than the home monitoring system itself. Limited evidence exists for optimal threshold identification [7]. Aggregated, large amounts of data gathered by telemonitoring have not been proven to be used effectively. Moreover, as mentioned, a clear definition and management guidelines for pulmonary exacerbation are lacking. As a next step, studies are ongoing to evaluate how to use the collected data without increasing harm or cost. This could utilize machine learning or developing a more specific model defining and predicting pulmonary exacerbations as well as standardized indications for antibiotic therapy and hospitalization.

Applications for Clinical Practice

CF patients suffer from frequent pulmonary exacerbations and close monitoring and appropriate treatment is necessary to prevent progressive decline of lung function. This study has shown no benefit of electronic home monitoring in CF patients based on symptoms and spirometry over usual care. However, this negative outcome may be due to the limitation of the current definition of pulmonary exacerbation and lack of a consensus management algorithm. Optimizing the definition of pulmonary exacerbation and protocoling management based on severity may improve future evaluations of electronic home monitoring. Electronic home monitoring may help identify patients requiring evaluation; however, clinicians should continue to manage CF patients with conventional tools including regular follow-up visits, thorough history taking, and appropriate use of antibiotics based on their clinical acumen.

—Minkyung Kwon, MD, Joel Roberson, MD, Drew Willey, MD, and Neal Patel, MD (Mayo Clinic Florida, Jacksonville, FL, except for Dr. Roberson, of Oakland University/ Beaumont Health, Royal Oak, MI)

Study Overview

Objective. To determine the effectiveness of asthma treatment using fluticasone furoate plus vilanterol in a setting that is closer to usual clinical practice.

Design. Open-label, parallel group, randomised controlled trial.

Setting and participants. The study was conducted at 74 general practice clinics in Salford and South Manchester, UK, between Nov 2012 and Dec 2016. Patients with a general practitioner’s diagnosis of symptomatic asthma and on maintenance inhaler therapy (either inhaled corticosteroid [ICS] alone or in combination with a long-acting bronchodilator [LABA]) were recruited. Patients with recent history of life-threatening asthma, COPD, or concomitant life-threatening disease were excluded. Participants were randomly assigned through a centralized randomization service and stratified by Asthma Control Test (ACT) score and by previous asthma maintenance therapy (ICS or ICS/LABA). Only those with an ACT score < 20 were included in the study.

Intervention. Patients were randomized to receive either a combination of fluticasone furoate and vilanterol (FF/VI) delivered by novel dry powder inhalation (DPI) (Ellipta) or to continue with their maintenance therapy. General practitioners provided care in their usual manner and could continuously optimize therapy according to their clinical opinion. Treatments were dispensed by community pharmacies in the usual way. Patients could modify their treatment and remain in the study. Those in the FF/VI group were allowed to change to other asthma medications and could stop taking FF/VI. Those in the usual care group were also allowed to alter medications, but could not initiate FF/VI.

Main outcome measures. The primary endpoint was ACT score at week 24 (the percentage of patients at week 24 with either an ACT score of 20 or greater or an increase of 3 or greater in the ACT score from baseline, termed responders). Safety endpoints included the incidence of serious pneumonias. The study utilized the Salford electronic medical record system, which allows near to real-time collection and monitoring of safety data. Secondary endpoints included ACT at various weeks, all asthma-related primary and secondary care contacts, annual rate of severe exacerbations, number of salbutamol inhalers dispensed, and time to modification or initial therapy.

Main results. 4233 patients were randomized, with 2119 patients randomized to usual care and 2114 randomized to the FF/VI group. 605 from the usual care group and 602 from the FF/VI group had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. 306 in the usual care group and 342 in the FF/VI group withdrew for various reasons, including adverse events, or were lost to follow-up or protocol deviations. Mean patient age was 50 years. Within the usual care group, 64% of patients received ICS/LABA combination and 36% received ICS only. Within the FF/VI group, 65% were prescribed 100 μg/25 μg FFI/VI and 35% were prescribed 200 μg/25 μg FF/VI. At week 24, the FF/VI group had 74% responders whereas the usual care group had 60% responders; the odds of being a responder with FF/VI was twice that of being a responder with usual care (OR 1.97; 95% CI 1.71–2.26, P < 0.001). Patients in the FF/VI group had a slightly higher incidence of pneumonia than did the usual care group (23 vs 16; incidence ratio 1.4, 95% CI 0.8–2.7). Also, those in the FF/VI group had an increase in the rate of primary care visits/contacts per year (9.7% increase, 95% CI 4.6%–15.0%).

Conclusion. In patients with a general practitioner’s diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined FF/VI improved asthma control without increasing the risk of serious adverse events when compared with optimized usual care.

Commentary

Woodcock et al conducted a pragmatic randomized controlled study. This innovative research method prospectively enrolled a large number of patients who were randomized to groups that could involve 1 or more interventions and who were then followed according to the treating physician’s usual practice. The patients’ experience was kept as close to everyday clinical practice care as possible to preserve the real-world nature of the study. The positive aspect of this innovative pragmatic research design is the inclusion of patients with varied disease severity and with comorbidities that are not well represented in conventional double-blind randomized controlled trials, such as patients with smoking history, obesity, or multiple comorbidities. In addition, an electronic health record system was used to track serious adverse events in near real-time and increased the accuracy of the data and minimized data loss.

While the pragmatic study design offers innovation, it also has some limitations. Effectiveness studies using a pragmatic approach are less controlled compared with traditional efficacy RCTs and are more prone to low medication compliance and high rates of follow-up loss. Further, Woodcock et al allowed patients to remain in the FF/VI group even though they may have stopped taking FF/VI. Indeed, in the FF/VI group, 463 (22%) of the 2114 patients changed their medication, and 381 (18%) switched to the usual care group. Patients were analyzed using intention to treat and thus were analyzed in the group to which they were initially randomized. This could have affected results, as a good proportion of patients in the FF/VI group were not actually taking the FF/VI. Within the usual care group, 376 (18%) of 2119 patients altered their medication and 3 (< 1%) switched to FF/VI, though this was prohibited. In routine care, adherence rates are expected to be low (20%–40%) and this is another possible weakness of the study; in closely monitored RCTs, adherence rates are around 80%–90%.

The authors did not include objective measures of the severity or types of asthma, which can be obtained using pulmonary function tests, eosinophil count, or other markers of inflammation. By identifying asthma patients via the general practitioner’s diagnosis, the study is more reflective of real life and primary care–driven; however, one cannot rule out accidental inclusion of patients who do not have asthma (which could include patients with post-infectious cough, vocal cord dysfunction, or anxiety) or patients who would not readily respond to typical asthma therapy (such as those with allergic bronchopulmonary aspergillosis or eosinophilic granulomatosis with polyangitis). In addition, the authors used only subjective measures to define control: ACT score by telephone. Other outcome measures included exacerbation rate, primary care physician visits, and time to exacerbation, which may be insensitive to detecting residual inflammation or severity of asthma. In lieu of objectively measuring the degree of airway obstruction or inflammation, the outcomes measured by the authors may not have comprehensively evaluated efficacy.

The open-label, intention-to-treat, and pragmatic design of the study may have generated major selection bias, despite the randomization. Because general practitioners who directly participated in the recruitment of the patients also monitored their treatment, volunteer or referral bias may have occurred. As the authors admitted, there were differences present in practice and treatment due to variation of training and education of the general practitioners. In addition, the current study was funded by a pharmaceutical company and the trial medication was dispensed free of cost, further generating bias.

Further consideration of the study medication also brings up questions about the study design. Combined therapy with low- to moderate-dose ICS/LABA is currently indicated for asthma patients with moderate persistent or higher severity asthma. The current US insurance system encourages management to begin with low-dose ICS before escalating to a combination of ICS/LABA. Given the previously published evidence of superiority for combined ICS/LABA over ICS alone on asthma control [2,3], inclusion criteria could have been limited only to patients who were already receiving ICS/LABA to more accurately equate the trial medication with the accepted standard medications. By including patients who were on ICS/LABA as well as those only on ICS (in usual care group, 64% were on ICS/LABA and 36% were on ICS) the likelihood of responders in the FF/VI group could have been inflated compared to usual care group. In addition, patients with a low severity of asthma symptoms, such as only intermittent asthma or mild persistent asthma, could have been overtreated by FF/VI per current guidelines. About 30% of the patients initially enrolled in the study had baseline ACT scores greater than 20, and some patients had less severe asthma as indicated by the treatment with ICS alone. The authors also included 2 different doses of fluticasone furoate in their study group.

It is of concern that the incidence of pneumonia with ICS/LABA in this study was slightly higher in the FF/VI than in the usual care group. Although it was not statistically significant in this study, the increased pneumonia risk with ICS has been observed in many other studies [4,5].

Applications for Clinical Practice

Fluticasone furoate plus vilanterol (FF/VI) can be a therapeutic option in patients with asthma, with a small increased risk for pneumonia that is similar to other types of inhaled corticosteroids. However, a stepwise therapeutic approach, following the published asthma treatment strategy [6], should be emphasized when escalating treatment to include FF/VI.

—Minkyung Kwon, MD, Joel Roberson, MD, and Neal Patel, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL (Drs. Kwon and Patel), and Department of Radiology, Oakland University/Beaumont Health, Royal Oak, MI (Dr. Roberson)

Study Overview

Objective. To determine the effectiveness of asthma treatment using fluticasone furoate plus vilanterol in a setting that is closer to usual clinical practice.

Design. Open-label, parallel group, randomised controlled trial.

Setting and participants. The study was conducted at 74 general practice clinics in Salford and South Manchester, UK, between Nov 2012 and Dec 2016. Patients with a general practitioner’s diagnosis of symptomatic asthma and on maintenance inhaler therapy (either inhaled corticosteroid [ICS] alone or in combination with a long-acting bronchodilator [LABA]) were recruited. Patients with recent history of life-threatening asthma, COPD, or concomitant life-threatening disease were excluded. Participants were randomly assigned through a centralized randomization service and stratified by Asthma Control Test (ACT) score and by previous asthma maintenance therapy (ICS or ICS/LABA). Only those with an ACT score < 20 were included in the study.

Intervention. Patients were randomized to receive either a combination of fluticasone furoate and vilanterol (FF/VI) delivered by novel dry powder inhalation (DPI) (Ellipta) or to continue with their maintenance therapy. General practitioners provided care in their usual manner and could continuously optimize therapy according to their clinical opinion. Treatments were dispensed by community pharmacies in the usual way. Patients could modify their treatment and remain in the study. Those in the FF/VI group were allowed to change to other asthma medications and could stop taking FF/VI. Those in the usual care group were also allowed to alter medications, but could not initiate FF/VI.

Main outcome measures. The primary endpoint was ACT score at week 24 (the percentage of patients at week 24 with either an ACT score of 20 or greater or an increase of 3 or greater in the ACT score from baseline, termed responders). Safety endpoints included the incidence of serious pneumonias. The study utilized the Salford electronic medical record system, which allows near to real-time collection and monitoring of safety data. Secondary endpoints included ACT at various weeks, all asthma-related primary and secondary care contacts, annual rate of severe exacerbations, number of salbutamol inhalers dispensed, and time to modification or initial therapy.

Main results. 4233 patients were randomized, with 2119 patients randomized to usual care and 2114 randomized to the FF/VI group. 605 from the usual care group and 602 from the FF/VI group had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. 306 in the usual care group and 342 in the FF/VI group withdrew for various reasons, including adverse events, or were lost to follow-up or protocol deviations. Mean patient age was 50 years. Within the usual care group, 64% of patients received ICS/LABA combination and 36% received ICS only. Within the FF/VI group, 65% were prescribed 100 μg/25 μg FFI/VI and 35% were prescribed 200 μg/25 μg FF/VI. At week 24, the FF/VI group had 74% responders whereas the usual care group had 60% responders; the odds of being a responder with FF/VI was twice that of being a responder with usual care (OR 1.97; 95% CI 1.71–2.26, P < 0.001). Patients in the FF/VI group had a slightly higher incidence of pneumonia than did the usual care group (23 vs 16; incidence ratio 1.4, 95% CI 0.8–2.7). Also, those in the FF/VI group had an increase in the rate of primary care visits/contacts per year (9.7% increase, 95% CI 4.6%–15.0%).

Conclusion. In patients with a general practitioner’s diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined FF/VI improved asthma control without increasing the risk of serious adverse events when compared with optimized usual care.

Commentary

Woodcock et al conducted a pragmatic randomized controlled study. This innovative research method prospectively enrolled a large number of patients who were randomized to groups that could involve 1 or more interventions and who were then followed according to the treating physician’s usual practice. The patients’ experience was kept as close to everyday clinical practice care as possible to preserve the real-world nature of the study. The positive aspect of this innovative pragmatic research design is the inclusion of patients with varied disease severity and with comorbidities that are not well represented in conventional double-blind randomized controlled trials, such as patients with smoking history, obesity, or multiple comorbidities. In addition, an electronic health record system was used to track serious adverse events in near real-time and increased the accuracy of the data and minimized data loss.

While the pragmatic study design offers innovation, it also has some limitations. Effectiveness studies using a pragmatic approach are less controlled compared with traditional efficacy RCTs and are more prone to low medication compliance and high rates of follow-up loss. Further, Woodcock et al allowed patients to remain in the FF/VI group even though they may have stopped taking FF/VI. Indeed, in the FF/VI group, 463 (22%) of the 2114 patients changed their medication, and 381 (18%) switched to the usual care group. Patients were analyzed using intention to treat and thus were analyzed in the group to which they were initially randomized. This could have affected results, as a good proportion of patients in the FF/VI group were not actually taking the FF/VI. Within the usual care group, 376 (18%) of 2119 patients altered their medication and 3 (< 1%) switched to FF/VI, though this was prohibited. In routine care, adherence rates are expected to be low (20%–40%) and this is another possible weakness of the study; in closely monitored RCTs, adherence rates are around 80%–90%.

The authors did not include objective measures of the severity or types of asthma, which can be obtained using pulmonary function tests, eosinophil count, or other markers of inflammation. By identifying asthma patients via the general practitioner’s diagnosis, the study is more reflective of real life and primary care–driven; however, one cannot rule out accidental inclusion of patients who do not have asthma (which could include patients with post-infectious cough, vocal cord dysfunction, or anxiety) or patients who would not readily respond to typical asthma therapy (such as those with allergic bronchopulmonary aspergillosis or eosinophilic granulomatosis with polyangitis). In addition, the authors used only subjective measures to define control: ACT score by telephone. Other outcome measures included exacerbation rate, primary care physician visits, and time to exacerbation, which may be insensitive to detecting residual inflammation or severity of asthma. In lieu of objectively measuring the degree of airway obstruction or inflammation, the outcomes measured by the authors may not have comprehensively evaluated efficacy.

The open-label, intention-to-treat, and pragmatic design of the study may have generated major selection bias, despite the randomization. Because general practitioners who directly participated in the recruitment of the patients also monitored their treatment, volunteer or referral bias may have occurred. As the authors admitted, there were differences present in practice and treatment due to variation of training and education of the general practitioners. In addition, the current study was funded by a pharmaceutical company and the trial medication was dispensed free of cost, further generating bias.

Further consideration of the study medication also brings up questions about the study design. Combined therapy with low- to moderate-dose ICS/LABA is currently indicated for asthma patients with moderate persistent or higher severity asthma. The current US insurance system encourages management to begin with low-dose ICS before escalating to a combination of ICS/LABA. Given the previously published evidence of superiority for combined ICS/LABA over ICS alone on asthma control [2,3], inclusion criteria could have been limited only to patients who were already receiving ICS/LABA to more accurately equate the trial medication with the accepted standard medications. By including patients who were on ICS/LABA as well as those only on ICS (in usual care group, 64% were on ICS/LABA and 36% were on ICS) the likelihood of responders in the FF/VI group could have been inflated compared to usual care group. In addition, patients with a low severity of asthma symptoms, such as only intermittent asthma or mild persistent asthma, could have been overtreated by FF/VI per current guidelines. About 30% of the patients initially enrolled in the study had baseline ACT scores greater than 20, and some patients had less severe asthma as indicated by the treatment with ICS alone. The authors also included 2 different doses of fluticasone furoate in their study group.

It is of concern that the incidence of pneumonia with ICS/LABA in this study was slightly higher in the FF/VI than in the usual care group. Although it was not statistically significant in this study, the increased pneumonia risk with ICS has been observed in many other studies [4,5].

Applications for Clinical Practice

Fluticasone furoate plus vilanterol (FF/VI) can be a therapeutic option in patients with asthma, with a small increased risk for pneumonia that is similar to other types of inhaled corticosteroids. However, a stepwise therapeutic approach, following the published asthma treatment strategy [6], should be emphasized when escalating treatment to include FF/VI.

—Minkyung Kwon, MD, Joel Roberson, MD, and Neal Patel, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL (Drs. Kwon and Patel), and Department of Radiology, Oakland University/Beaumont Health, Royal Oak, MI (Dr. Roberson)

Study Overview

Objective. To determine the effectiveness of asthma treatment using fluticasone furoate plus vilanterol in a setting that is closer to usual clinical practice.

Design. Open-label, parallel group, randomised controlled trial.

Setting and participants. The study was conducted at 74 general practice clinics in Salford and South Manchester, UK, between Nov 2012 and Dec 2016. Patients with a general practitioner’s diagnosis of symptomatic asthma and on maintenance inhaler therapy (either inhaled corticosteroid [ICS] alone or in combination with a long-acting bronchodilator [LABA]) were recruited. Patients with recent history of life-threatening asthma, COPD, or concomitant life-threatening disease were excluded. Participants were randomly assigned through a centralized randomization service and stratified by Asthma Control Test (ACT) score and by previous asthma maintenance therapy (ICS or ICS/LABA). Only those with an ACT score < 20 were included in the study.

Intervention. Patients were randomized to receive either a combination of fluticasone furoate and vilanterol (FF/VI) delivered by novel dry powder inhalation (DPI) (Ellipta) or to continue with their maintenance therapy. General practitioners provided care in their usual manner and could continuously optimize therapy according to their clinical opinion. Treatments were dispensed by community pharmacies in the usual way. Patients could modify their treatment and remain in the study. Those in the FF/VI group were allowed to change to other asthma medications and could stop taking FF/VI. Those in the usual care group were also allowed to alter medications, but could not initiate FF/VI.

Main outcome measures. The primary endpoint was ACT score at week 24 (the percentage of patients at week 24 with either an ACT score of 20 or greater or an increase of 3 or greater in the ACT score from baseline, termed responders). Safety endpoints included the incidence of serious pneumonias. The study utilized the Salford electronic medical record system, which allows near to real-time collection and monitoring of safety data. Secondary endpoints included ACT at various weeks, all asthma-related primary and secondary care contacts, annual rate of severe exacerbations, number of salbutamol inhalers dispensed, and time to modification or initial therapy.

Main results. 4233 patients were randomized, with 2119 patients randomized to usual care and 2114 randomized to the FF/VI group. 605 from the usual care group and 602 from the FF/VI group had a baseline ACT score greater than or equal to 20 and were thus excluded from the primary effectiveness analysis population. 306 in the usual care group and 342 in the FF/VI group withdrew for various reasons, including adverse events, or were lost to follow-up or protocol deviations. Mean patient age was 50 years. Within the usual care group, 64% of patients received ICS/LABA combination and 36% received ICS only. Within the FF/VI group, 65% were prescribed 100 μg/25 μg FFI/VI and 35% were prescribed 200 μg/25 μg FF/VI. At week 24, the FF/VI group had 74% responders whereas the usual care group had 60% responders; the odds of being a responder with FF/VI was twice that of being a responder with usual care (OR 1.97; 95% CI 1.71–2.26, P < 0.001). Patients in the FF/VI group had a slightly higher incidence of pneumonia than did the usual care group (23 vs 16; incidence ratio 1.4, 95% CI 0.8–2.7). Also, those in the FF/VI group had an increase in the rate of primary care visits/contacts per year (9.7% increase, 95% CI 4.6%–15.0%).

Conclusion. In patients with a general practitioner’s diagnosis of symptomatic asthma and on maintenance inhaler therapy, initiation of a once-daily treatment regimen of combined FF/VI improved asthma control without increasing the risk of serious adverse events when compared with optimized usual care.

Commentary

Woodcock et al conducted a pragmatic randomized controlled study. This innovative research method prospectively enrolled a large number of patients who were randomized to groups that could involve 1 or more interventions and who were then followed according to the treating physician’s usual practice. The patients’ experience was kept as close to everyday clinical practice care as possible to preserve the real-world nature of the study. The positive aspect of this innovative pragmatic research design is the inclusion of patients with varied disease severity and with comorbidities that are not well represented in conventional double-blind randomized controlled trials, such as patients with smoking history, obesity, or multiple comorbidities. In addition, an electronic health record system was used to track serious adverse events in near real-time and increased the accuracy of the data and minimized data loss.

While the pragmatic study design offers innovation, it also has some limitations. Effectiveness studies using a pragmatic approach are less controlled compared with traditional efficacy RCTs and are more prone to low medication compliance and high rates of follow-up loss. Further, Woodcock et al allowed patients to remain in the FF/VI group even though they may have stopped taking FF/VI. Indeed, in the FF/VI group, 463 (22%) of the 2114 patients changed their medication, and 381 (18%) switched to the usual care group. Patients were analyzed using intention to treat and thus were analyzed in the group to which they were initially randomized. This could have affected results, as a good proportion of patients in the FF/VI group were not actually taking the FF/VI. Within the usual care group, 376 (18%) of 2119 patients altered their medication and 3 (< 1%) switched to FF/VI, though this was prohibited. In routine care, adherence rates are expected to be low (20%–40%) and this is another possible weakness of the study; in closely monitored RCTs, adherence rates are around 80%–90%.

The authors did not include objective measures of the severity or types of asthma, which can be obtained using pulmonary function tests, eosinophil count, or other markers of inflammation. By identifying asthma patients via the general practitioner’s diagnosis, the study is more reflective of real life and primary care–driven; however, one cannot rule out accidental inclusion of patients who do not have asthma (which could include patients with post-infectious cough, vocal cord dysfunction, or anxiety) or patients who would not readily respond to typical asthma therapy (such as those with allergic bronchopulmonary aspergillosis or eosinophilic granulomatosis with polyangitis). In addition, the authors used only subjective measures to define control: ACT score by telephone. Other outcome measures included exacerbation rate, primary care physician visits, and time to exacerbation, which may be insensitive to detecting residual inflammation or severity of asthma. In lieu of objectively measuring the degree of airway obstruction or inflammation, the outcomes measured by the authors may not have comprehensively evaluated efficacy.

The open-label, intention-to-treat, and pragmatic design of the study may have generated major selection bias, despite the randomization. Because general practitioners who directly participated in the recruitment of the patients also monitored their treatment, volunteer or referral bias may have occurred. As the authors admitted, there were differences present in practice and treatment due to variation of training and education of the general practitioners. In addition, the current study was funded by a pharmaceutical company and the trial medication was dispensed free of cost, further generating bias.

Further consideration of the study medication also brings up questions about the study design. Combined therapy with low- to moderate-dose ICS/LABA is currently indicated for asthma patients with moderate persistent or higher severity asthma. The current US insurance system encourages management to begin with low-dose ICS before escalating to a combination of ICS/LABA. Given the previously published evidence of superiority for combined ICS/LABA over ICS alone on asthma control [2,3], inclusion criteria could have been limited only to patients who were already receiving ICS/LABA to more accurately equate the trial medication with the accepted standard medications. By including patients who were on ICS/LABA as well as those only on ICS (in usual care group, 64% were on ICS/LABA and 36% were on ICS) the likelihood of responders in the FF/VI group could have been inflated compared to usual care group. In addition, patients with a low severity of asthma symptoms, such as only intermittent asthma or mild persistent asthma, could have been overtreated by FF/VI per current guidelines. About 30% of the patients initially enrolled in the study had baseline ACT scores greater than 20, and some patients had less severe asthma as indicated by the treatment with ICS alone. The authors also included 2 different doses of fluticasone furoate in their study group.

It is of concern that the incidence of pneumonia with ICS/LABA in this study was slightly higher in the FF/VI than in the usual care group. Although it was not statistically significant in this study, the increased pneumonia risk with ICS has been observed in many other studies [4,5].

Applications for Clinical Practice

Fluticasone furoate plus vilanterol (FF/VI) can be a therapeutic option in patients with asthma, with a small increased risk for pneumonia that is similar to other types of inhaled corticosteroids. However, a stepwise therapeutic approach, following the published asthma treatment strategy [6], should be emphasized when escalating treatment to include FF/VI.

—Minkyung Kwon, MD, Joel Roberson, MD, and Neal Patel, MD, Pulmonary and Critical Care Medicine, Mayo Clinic Florida, Jacksonville, FL (Drs. Kwon and Patel), and Department of Radiology, Oakland University/Beaumont Health, Royal Oak, MI (Dr. Roberson)

Study Overview

Objective. To assess the effects of oral corticosteroids for acute lower respiratory tract infection in adults without asthma or COPD.

Design. Multi-center, placebo-controlled, randomized clinical trial.

Setting and participants. This study was conducted at 4 UK centers (the Universities of Bristol, Southampton, Nottingham, and Oxford) between July 2013 and October 2014. Patients with acute cough (≤ 28 days) and at least 1 of the following lower respiratory tract symptoms (phlegm, chest pain, wheezing, or shortness of breath) were recruited by family physicians and nurses. Patients with chronic pulmonary disease, who had received asthma medication in the past 5 years, required hospital admission, or required same-day antibiotics were excluded. Patients were randomized by variable block size into prednisolone or placebo groups in a 1:1 ratio, stratified by center.

Intervention. Participants were asked to take 2 tablets of either 20-mg oral prednisolone or placebo tablets once daily for 5 days. The medications, which looked and tasted identical, were packaged into numbered packs by an independent pharmacist and were delivered to the family practices to be distributed to the enrolled patients. Participants were invited to report daily, using web or paper version, the severity of symptoms using a scale 0 to 6, along with twice-daily peak flow, for 28 days or until symptom resolution. Participants received shopping vouchers. Medical notes were reviewed at 3 months for new diagnosis of asthma, chronic obstructive pulmonary disease, whooping cough, and lung cancer.

 Main outcome measures . The primary outcomes were the duration of moderately bad or worse cough (defined as the number of days from randomization to the last day with a score of at least 3 points prior to at least 2 consecutive days with a score of less than 3, up to a maximum of 28 days); and the mean severity score (range 0–6) of the 6 main symptoms (cough, phlegm, shortness of breath, sleep disturbance, feeling generally unwell, and activity disturbance) on days 2 to 4.

Main results. 401 patients were randomized; 25 patients were lost to follow-up, leaving 173 in prednisolone group and 161 in placebo group for analysis. The prednisolone group was slightly more likely to be male, older, and to have received an influenza vaccine. 96% were white. Symptom diaries were returned by 94% of patients. For primary outcome 1, duration of moderately bad or worse cough, the median time to recovery from moderately bad or worse cough was 5 days (interquartile range, 3–8 days) in both groups. There was no difference after sensitivity analysis (multiple imputation of missing data, per-protocol analysis, and adjusting for day of recruitment). Primary outcome 2, the mean symptom severity score, after adjustment for center and baseline measure, was lower (hazard ratio, –0.20) in the prednisolone group compared with the placebo group; however, after secondary additional adjustment for age, sex, influenza vaccine, and smoking, the difference was not statistically significant. Secondary outcomes included total duration and severity of each symptom up to 28 days, duration of abnormal peak flow up to 28 days, cough duration of any severity up to 56 days, antibiotic use, patient satisfaction, adverse events were not different between the two groups. There were no new urinary or visual symptoms and none of the patients reporting fatigue, thirst, or dry throat had diabetes.

Conclusion. Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity.

Commentary

This study by Hay et al prospectively recruited patients with acute respiratory illness presenting to an outpatient setting within multiple centers for a placebo-controlled randomized study to evaluate the effectiveness of oral corticosteroids for acute lower respiratory tract infection. Patients with pre-existing lung disease such as asthma or COPD were excluded. This study showed moderate-dose oral prednisolone (20 mg twice a day for 5 days) did not reduce the duration of cough, and there was no statistically significant differences in primary and secondary outcomes between the 2 groups.

The beneficial effect of corticosteroids is thought to be due to its anti-inflammatory effect and decreasing harmful cytokines, which can be elevated during acute respiratory illness. In patients with severe pneumonia, patients potentially benefitted from corticosteroids by achieving clinical stability faster, reducing risk for treatment failure or ARDS and reducing hospital length of stay. However, corticosteroids are associated with hyperglycemia, myopathy, superinfection, osteopenia, and increased risk for gastrointestinal bleeding [1]. Corticosteroids have shown benefit repeatedly in patients with pneumonia severe enough to require hospitalization or intensive care unit stay [2–7].

The use of oral corticosteroids in non-critical acute respiratory tract illness without underlying obstructive lung disease has been a somewhat common practice (15%) [8]. However, no study to date firmly supports the use of oral corticosteroids in this patient group. A recently published randomized study attempted to determine if there is a benefit of oral dexamethasone in patients with acute sore throat, and found none [9]. No randomized controlled data has been published on the outpatient use of oral corticosteroids for acute lower respiratory illness.

The current study offers further evidence against the use of oral corticosteroids for acute, non-critical inflammation of the respiratory tract in nonasthmatic patients. Strengths of the study include its blinded and randomized study design and large number of patients. However, there are some limitations. Acute lower respiratory infection is associated with a wide spectrum of causative organisms and severity. It is possible that the beneficial effects of corticosteroids are only measurable when disease severity is high and there will be a systemic inflammatory response. In addition, outcome measurement was limited to a few items, namely patient-reported symptom score and duration. Furthermore, they measured the peak flow adjunctively. Without underlying airway hyperreactivity, substantial differences in peak flow are unlikely to be evident, limiting the usefulness of this as an indicator of disease in patients without chronic pulmonary disease.

Other study limitations include low patient recruitment rate, a large number of patients who did not have moderately bad cough at presentation or during the first 2 days, absence of baseline biomarkers (such as inflammatory, microbiological, spirometric or radiographic) and patient-reported outcome measures, and a sample largely homogenous in ethnicity with a small number of smokers. It is unclear whether similar results could be achieved in a more diverse population and with a greater percentage of smokers. In addition, although overall both groups were well balanced, including the number of patients taking over-the-counter cough suppressants and delayed antibiotics, the tracking of other concurrent therapies such as NSAIDs or acetaminophen was not included in the study design and the type of antibiotic was not tabulated. Such concurrent drugs could have masked a true benefit of oral corticosteroids.

Applications for Clinical Practice

This study will help prevent excessive prescription of oral corticosteroids for acute minor lower respiratory infection that requires only outpatient treatment. However, the evidence is limited to patients in stable condition. Patients with more severe acute lower respiratory infection, such as patients requiring hospitalization, may still benefit from a short course of oral corticosteroids. Furthermore, patients with underlying obstructive airways disease such as asthma or COPD should still be considered for oral corticosteroid therapy depending on their clinical circumstances.

—Minkyung Kwon, MD,  Joel Roberson, MD, and Jack Leventhal, MD,
Pulmonary and Critical Care Medicine,Mayo Clini c Florida, Jacksonville, FL (Drs. Kwon andLeventhal), and Department of Radiology, Oakland University Beaumont Hospital, Royal Oak, MI (Dr. Roberson)

Study Overview

Objective. To assess the effects of oral corticosteroids for acute lower respiratory tract infection in adults without asthma or COPD.

Design. Multi-center, placebo-controlled, randomized clinical trial.

Setting and participants. This study was conducted at 4 UK centers (the Universities of Bristol, Southampton, Nottingham, and Oxford) between July 2013 and October 2014. Patients with acute cough (≤ 28 days) and at least 1 of the following lower respiratory tract symptoms (phlegm, chest pain, wheezing, or shortness of breath) were recruited by family physicians and nurses. Patients with chronic pulmonary disease, who had received asthma medication in the past 5 years, required hospital admission, or required same-day antibiotics were excluded. Patients were randomized by variable block size into prednisolone or placebo groups in a 1:1 ratio, stratified by center.

Intervention. Participants were asked to take 2 tablets of either 20-mg oral prednisolone or placebo tablets once daily for 5 days. The medications, which looked and tasted identical, were packaged into numbered packs by an independent pharmacist and were delivered to the family practices to be distributed to the enrolled patients. Participants were invited to report daily, using web or paper version, the severity of symptoms using a scale 0 to 6, along with twice-daily peak flow, for 28 days or until symptom resolution. Participants received shopping vouchers. Medical notes were reviewed at 3 months for new diagnosis of asthma, chronic obstructive pulmonary disease, whooping cough, and lung cancer.

 Main outcome measures . The primary outcomes were the duration of moderately bad or worse cough (defined as the number of days from randomization to the last day with a score of at least 3 points prior to at least 2 consecutive days with a score of less than 3, up to a maximum of 28 days); and the mean severity score (range 0–6) of the 6 main symptoms (cough, phlegm, shortness of breath, sleep disturbance, feeling generally unwell, and activity disturbance) on days 2 to 4.

Main results. 401 patients were randomized; 25 patients were lost to follow-up, leaving 173 in prednisolone group and 161 in placebo group for analysis. The prednisolone group was slightly more likely to be male, older, and to have received an influenza vaccine. 96% were white. Symptom diaries were returned by 94% of patients. For primary outcome 1, duration of moderately bad or worse cough, the median time to recovery from moderately bad or worse cough was 5 days (interquartile range, 3–8 days) in both groups. There was no difference after sensitivity analysis (multiple imputation of missing data, per-protocol analysis, and adjusting for day of recruitment). Primary outcome 2, the mean symptom severity score, after adjustment for center and baseline measure, was lower (hazard ratio, –0.20) in the prednisolone group compared with the placebo group; however, after secondary additional adjustment for age, sex, influenza vaccine, and smoking, the difference was not statistically significant. Secondary outcomes included total duration and severity of each symptom up to 28 days, duration of abnormal peak flow up to 28 days, cough duration of any severity up to 56 days, antibiotic use, patient satisfaction, adverse events were not different between the two groups. There were no new urinary or visual symptoms and none of the patients reporting fatigue, thirst, or dry throat had diabetes.

Conclusion. Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity.

Commentary

This study by Hay et al prospectively recruited patients with acute respiratory illness presenting to an outpatient setting within multiple centers for a placebo-controlled randomized study to evaluate the effectiveness of oral corticosteroids for acute lower respiratory tract infection. Patients with pre-existing lung disease such as asthma or COPD were excluded. This study showed moderate-dose oral prednisolone (20 mg twice a day for 5 days) did not reduce the duration of cough, and there was no statistically significant differences in primary and secondary outcomes between the 2 groups.

The beneficial effect of corticosteroids is thought to be due to its anti-inflammatory effect and decreasing harmful cytokines, which can be elevated during acute respiratory illness. In patients with severe pneumonia, patients potentially benefitted from corticosteroids by achieving clinical stability faster, reducing risk for treatment failure or ARDS and reducing hospital length of stay. However, corticosteroids are associated with hyperglycemia, myopathy, superinfection, osteopenia, and increased risk for gastrointestinal bleeding [1]. Corticosteroids have shown benefit repeatedly in patients with pneumonia severe enough to require hospitalization or intensive care unit stay [2–7].

The use of oral corticosteroids in non-critical acute respiratory tract illness without underlying obstructive lung disease has been a somewhat common practice (15%) [8]. However, no study to date firmly supports the use of oral corticosteroids in this patient group. A recently published randomized study attempted to determine if there is a benefit of oral dexamethasone in patients with acute sore throat, and found none [9]. No randomized controlled data has been published on the outpatient use of oral corticosteroids for acute lower respiratory illness.

The current study offers further evidence against the use of oral corticosteroids for acute, non-critical inflammation of the respiratory tract in nonasthmatic patients. Strengths of the study include its blinded and randomized study design and large number of patients. However, there are some limitations. Acute lower respiratory infection is associated with a wide spectrum of causative organisms and severity. It is possible that the beneficial effects of corticosteroids are only measurable when disease severity is high and there will be a systemic inflammatory response. In addition, outcome measurement was limited to a few items, namely patient-reported symptom score and duration. Furthermore, they measured the peak flow adjunctively. Without underlying airway hyperreactivity, substantial differences in peak flow are unlikely to be evident, limiting the usefulness of this as an indicator of disease in patients without chronic pulmonary disease.

Other study limitations include low patient recruitment rate, a large number of patients who did not have moderately bad cough at presentation or during the first 2 days, absence of baseline biomarkers (such as inflammatory, microbiological, spirometric or radiographic) and patient-reported outcome measures, and a sample largely homogenous in ethnicity with a small number of smokers. It is unclear whether similar results could be achieved in a more diverse population and with a greater percentage of smokers. In addition, although overall both groups were well balanced, including the number of patients taking over-the-counter cough suppressants and delayed antibiotics, the tracking of other concurrent therapies such as NSAIDs or acetaminophen was not included in the study design and the type of antibiotic was not tabulated. Such concurrent drugs could have masked a true benefit of oral corticosteroids.

Applications for Clinical Practice

This study will help prevent excessive prescription of oral corticosteroids for acute minor lower respiratory infection that requires only outpatient treatment. However, the evidence is limited to patients in stable condition. Patients with more severe acute lower respiratory infection, such as patients requiring hospitalization, may still benefit from a short course of oral corticosteroids. Furthermore, patients with underlying obstructive airways disease such as asthma or COPD should still be considered for oral corticosteroid therapy depending on their clinical circumstances.

—Minkyung Kwon, MD,  Joel Roberson, MD, and Jack Leventhal, MD,
Pulmonary and Critical Care Medicine,Mayo Clini c Florida, Jacksonville, FL (Drs. Kwon andLeventhal), and Department of Radiology, Oakland University Beaumont Hospital, Royal Oak, MI (Dr. Roberson)

Study Overview

Objective. To assess the effects of oral corticosteroids for acute lower respiratory tract infection in adults without asthma or COPD.

Design. Multi-center, placebo-controlled, randomized clinical trial.

Setting and participants. This study was conducted at 4 UK centers (the Universities of Bristol, Southampton, Nottingham, and Oxford) between July 2013 and October 2014. Patients with acute cough (≤ 28 days) and at least 1 of the following lower respiratory tract symptoms (phlegm, chest pain, wheezing, or shortness of breath) were recruited by family physicians and nurses. Patients with chronic pulmonary disease, who had received asthma medication in the past 5 years, required hospital admission, or required same-day antibiotics were excluded. Patients were randomized by variable block size into prednisolone or placebo groups in a 1:1 ratio, stratified by center.

Intervention. Participants were asked to take 2 tablets of either 20-mg oral prednisolone or placebo tablets once daily for 5 days. The medications, which looked and tasted identical, were packaged into numbered packs by an independent pharmacist and were delivered to the family practices to be distributed to the enrolled patients. Participants were invited to report daily, using web or paper version, the severity of symptoms using a scale 0 to 6, along with twice-daily peak flow, for 28 days or until symptom resolution. Participants received shopping vouchers. Medical notes were reviewed at 3 months for new diagnosis of asthma, chronic obstructive pulmonary disease, whooping cough, and lung cancer.

 Main outcome measures . The primary outcomes were the duration of moderately bad or worse cough (defined as the number of days from randomization to the last day with a score of at least 3 points prior to at least 2 consecutive days with a score of less than 3, up to a maximum of 28 days); and the mean severity score (range 0–6) of the 6 main symptoms (cough, phlegm, shortness of breath, sleep disturbance, feeling generally unwell, and activity disturbance) on days 2 to 4.

Main results. 401 patients were randomized; 25 patients were lost to follow-up, leaving 173 in prednisolone group and 161 in placebo group for analysis. The prednisolone group was slightly more likely to be male, older, and to have received an influenza vaccine. 96% were white. Symptom diaries were returned by 94% of patients. For primary outcome 1, duration of moderately bad or worse cough, the median time to recovery from moderately bad or worse cough was 5 days (interquartile range, 3–8 days) in both groups. There was no difference after sensitivity analysis (multiple imputation of missing data, per-protocol analysis, and adjusting for day of recruitment). Primary outcome 2, the mean symptom severity score, after adjustment for center and baseline measure, was lower (hazard ratio, –0.20) in the prednisolone group compared with the placebo group; however, after secondary additional adjustment for age, sex, influenza vaccine, and smoking, the difference was not statistically significant. Secondary outcomes included total duration and severity of each symptom up to 28 days, duration of abnormal peak flow up to 28 days, cough duration of any severity up to 56 days, antibiotic use, patient satisfaction, adverse events were not different between the two groups. There were no new urinary or visual symptoms and none of the patients reporting fatigue, thirst, or dry throat had diabetes.

Conclusion. Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity.

Commentary

This study by Hay et al prospectively recruited patients with acute respiratory illness presenting to an outpatient setting within multiple centers for a placebo-controlled randomized study to evaluate the effectiveness of oral corticosteroids for acute lower respiratory tract infection. Patients with pre-existing lung disease such as asthma or COPD were excluded. This study showed moderate-dose oral prednisolone (20 mg twice a day for 5 days) did not reduce the duration of cough, and there was no statistically significant differences in primary and secondary outcomes between the 2 groups.

The beneficial effect of corticosteroids is thought to be due to its anti-inflammatory effect and decreasing harmful cytokines, which can be elevated during acute respiratory illness. In patients with severe pneumonia, patients potentially benefitted from corticosteroids by achieving clinical stability faster, reducing risk for treatment failure or ARDS and reducing hospital length of stay. However, corticosteroids are associated with hyperglycemia, myopathy, superinfection, osteopenia, and increased risk for gastrointestinal bleeding [1]. Corticosteroids have shown benefit repeatedly in patients with pneumonia severe enough to require hospitalization or intensive care unit stay [2–7].

The use of oral corticosteroids in non-critical acute respiratory tract illness without underlying obstructive lung disease has been a somewhat common practice (15%) [8]. However, no study to date firmly supports the use of oral corticosteroids in this patient group. A recently published randomized study attempted to determine if there is a benefit of oral dexamethasone in patients with acute sore throat, and found none [9]. No randomized controlled data has been published on the outpatient use of oral corticosteroids for acute lower respiratory illness.

The current study offers further evidence against the use of oral corticosteroids for acute, non-critical inflammation of the respiratory tract in nonasthmatic patients. Strengths of the study include its blinded and randomized study design and large number of patients. However, there are some limitations. Acute lower respiratory infection is associated with a wide spectrum of causative organisms and severity. It is possible that the beneficial effects of corticosteroids are only measurable when disease severity is high and there will be a systemic inflammatory response. In addition, outcome measurement was limited to a few items, namely patient-reported symptom score and duration. Furthermore, they measured the peak flow adjunctively. Without underlying airway hyperreactivity, substantial differences in peak flow are unlikely to be evident, limiting the usefulness of this as an indicator of disease in patients without chronic pulmonary disease.

Other study limitations include low patient recruitment rate, a large number of patients who did not have moderately bad cough at presentation or during the first 2 days, absence of baseline biomarkers (such as inflammatory, microbiological, spirometric or radiographic) and patient-reported outcome measures, and a sample largely homogenous in ethnicity with a small number of smokers. It is unclear whether similar results could be achieved in a more diverse population and with a greater percentage of smokers. In addition, although overall both groups were well balanced, including the number of patients taking over-the-counter cough suppressants and delayed antibiotics, the tracking of other concurrent therapies such as NSAIDs or acetaminophen was not included in the study design and the type of antibiotic was not tabulated. Such concurrent drugs could have masked a true benefit of oral corticosteroids.

Applications for Clinical Practice

This study will help prevent excessive prescription of oral corticosteroids for acute minor lower respiratory infection that requires only outpatient treatment. However, the evidence is limited to patients in stable condition. Patients with more severe acute lower respiratory infection, such as patients requiring hospitalization, may still benefit from a short course of oral corticosteroids. Furthermore, patients with underlying obstructive airways disease such as asthma or COPD should still be considered for oral corticosteroid therapy depending on their clinical circumstances.

—Minkyung Kwon, MD,  Joel Roberson, MD, and Jack Leventhal, MD,
Pulmonary and Critical Care Medicine,Mayo Clini c Florida, Jacksonville, FL (Drs. Kwon andLeventhal), and Department of Radiology, Oakland University Beaumont Hospital, Royal Oak, MI (Dr. Roberson)